Mechanisms Associated with PINK1 Mutations in Parkinson's Disease

Mechanisms Associated with PINK1 Mutations in... | F1000Research "use strict";function _typeof(t){return(_typeof="function"==typeof Symbol&&"symbol"==typeof Symbol.iterator?function(t){return typeof t}:function(t){return t&&"function"==typeof Symbol&&t.constructor===Symbol&&t!==Symbol.prototype?"symbol":typeof t})(t)}!function(){var t=function(){var t,e,o=[],n=window,r=n;for(;r;){try{if(r.frames.__tcfapiLocator){t=r;break}}catch(t){}if(r===n.top)break;r=r.parent}t||(!function t(){var e=n.document,o=!!n.frames.__tcfapiLocator;if(!o)if(e.body){var r=e.createElement("iframe");r.style.cssText="display:none",r.name="__tcfapiLocator",e.body.appendChild(r)}else setTimeout(t,5);return!o}(),n.__tcfapi=function(){for(var t=arguments.length,n=new Array(t),r=0;r 3&&2===parseInt(n[1],10)&&"boolean"==typeof n[3]&&(e=n[3],"function"==typeof n[2]&&n[2]("set",!0)):"ping"===n[0]?"function"==typeof n[2]&&n[2]({gdprApplies:e,cmpLoaded:!1,cmpStatus:"stub"}):o.push(n)},n.addEventListener("message",(function(t){var e="string"==typeof t.data,o={};if(e)try{o=JSON.parse(t.data)}catch(t){}else o=t.data;var n="object"===_typeof(o)&&null!==o?o.__tcfapiCall:null;n&&window.__tcfapi(n.command,n.version,(function(o,r){var a={__tcfapiReturn:{returnValue:o,success:r,callId:n.callId}};t&&t.source&&t.source.postMessage&&t.source.postMessage(e?JSON.stringify(a):a,"*")}),n.parameter)}),!1))};"undefined"!=typeof module?module.exports=t:t()}(); dataLayer = dataLayer || []; // Standard GTM initialization - Google Consent Mode handles consent automatically (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start': new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0], j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src= 'https://www.googletagmanager.com/gtm.js?id='+i+dl+ '>m_auth=hzk0Vc3qFsQYhCrIoHz68A>m_preview=env-1>m_cookies_win=x';f.parentNode.insertBefore(j,f); })(window,document,'script','dataLayer','GTM-MWFK8L5J'); ;window.NREUM||(NREUM={});NREUM.init={distributed_tracing:{enabled:true},privacy:{cookies_enabled:true},ajax:{deny_list:["bam.nr-data.net"]}}; ;NREUM.loader_config={accountID:"438030",trustKey:"438030",agentID:"772317073",licenseKey:"97f8f67f26",applicationID:"772317073"} ;NREUM.info={beacon:"bam.nr-data.net",errorBeacon:"bam.nr-data.net",licenseKey:"97f8f67f26",applicationID:"772317073",sa:1} ;/*! For license information please see nr-loader-spa-1.236.0.min.js.LICENSE.txt */ (()=>{"use strict";var e,t,r={5763:(e,t,r)=>{r.d(t,{P_:()=>l,Mt:()=>g,C5:()=>s,DL:()=>v,OP:()=>T,lF:()=>D,Yu:()=>y,Dg:()=>h,CX:()=>c,GE:()=>b,sU:()=>_});var n=r(8632),i=r(9567);const o={beacon:n.ce.beacon,errorBeacon:n.ce.errorBeacon,licenseKey:void 0,applicationID:void 0,sa:void 0,queueTime:void 0,applicationTime:void 0,ttGuid:void 0,user:void 0,account:void 0,product:void 0,extra:void 0,jsAttributes:{},userAttributes:void 0,atts:void 0,transactionName:void 0,tNamePlain:void 0},a={};function s(e){if(!e)throw new Error("All info objects require an agent identifier!");if(!a[e])throw new Error("Info for ".concat(e," was never set"));return a[e]}function c(e,t){if(!e)throw new Error("All info objects require an agent identifier!");a[e]=(0,i.D)(t,o),(0,n.Qy)(e,a[e],"info")}var u=r(7056);const d=()=>{const e={blockSelector:"[data-nr-block]",maskInputOptions:{password:!0}};return{allow_bfcache:!0,privacy:{cookies_enabled:!0},ajax:{deny_list:void 0,enabled:!0,harvestTimeSeconds:10},distributed_tracing:{enabled:void 0,exclude_newrelic_header:void 0,cors_use_newrelic_header:void 0,cors_use_tracecontext_headers:void 0,allowed_origins:void 0},session:{domain:void 0,expiresMs:u.oD,inactiveMs:u.Hb},ssl:void 0,obfuscate:void 0,jserrors:{enabled:!0,harvestTimeSeconds:10},metrics:{enabled:!0},page_action:{enabled:!0,harvestTimeSeconds:30},page_view_event:{enabled:!0},page_view_timing:{enabled:!0,harvestTimeSeconds:30,long_task:!1},session_trace:{enabled:!0,harvestTimeSeconds:10},harvest:{tooManyRequestsDelay:60},session_replay:{enabled:!1,harvestTimeSeconds:60,sampleRate:.1,errorSampleRate:.1,maskTextSelector:"*",maskAllInputs:!0,get blockClass(){return"nr-block"},get ignoreClass(){return"nr-ignore"},get maskTextClass(){return"nr-mask"},get blockSelector(){return e.blockSelector},set blockSelector(t){e.blockSelector+=",".concat(t)},get maskInputOptions(){return e.maskInputOptions},set maskInputOptions(t){e.maskInputOptions={...t,password:!0}}},spa:{enabled:!0,harvestTimeSeconds:10}}},f={};function l(e){if(!e)throw new Error("All configuration objects require an agent identifier!");if(!f[e])throw new Error("Configuration for ".concat(e," was never set"));return f[e]}function h(e,t){if(!e)throw new Error("All configuration objects require an agent identifier!");f[e]=(0,i.D)(t,d()),(0,n.Qy)(e,f[e],"config")}function g(e,t){if(!e)throw new Error("All configuration objects require an agent identifier!");var r=l(e);if(r){for(var n=t.split("."),i=0;i {r.d(t,{D:()=>i});var n=r(50);function i(e,t){try{if(!e||"object"!=typeof e)return(0,n.Z)("Setting a Configurable requires an object as input");if(!t||"object"!=typeof t)return(0,n.Z)("Setting a Configurable requires a model to set its initial properties");const r=Object.create(Object.getPrototypeOf(t),Object.getOwnPropertyDescriptors(t)),o=0===Object.keys(r).length?e:r;for(let a in o)if(void 0!==e[a])try{"object"==typeof e[a]&&"object"==typeof t[a]?r[a]=i(e[a],t[a]):r[a]=e[a]}catch(e){(0,n.Z)("An error occurred while setting a property of a Configurable",e)}return r}catch(e){(0,n.Z)("An error occured while setting a Configurable",e)}}},6818:(e,t,r)=>{r.d(t,{Re:()=>i,gF:()=>o,q4:()=>n});const n="1.236.0",i="PROD",o="CDN"},385:(e,t,r)=>{r.d(t,{FN:()=>a,IF:()=>u,Nk:()=>f,Tt:()=>s,_A:()=>o,il:()=>n,pL:()=>c,v6:()=>i,w1:()=>d});const n="undefined"!=typeof window&&!!window.document,i="undefined"!=typeof WorkerGlobalScope&&("undefined"!=typeof self&&self instanceof WorkerGlobalScope&&self.navigator instanceof WorkerNavigator||"undefined"!=typeof globalThis&&globalThis instanceof WorkerGlobalScope&&globalThis.navigator instanceof WorkerNavigator),o=n?window:"undefined"!=typeof WorkerGlobalScope&&("undefined"!=typeof self&&self instanceof WorkerGlobalScope&&self||"undefined"!=typeof globalThis&&globalThis instanceof WorkerGlobalScope&&globalThis),a=""+o?.location,s=/iPad|iPhone|iPod/.test(navigator.userAgent),c=s&&"undefined"==typeof SharedWorker,u=(()=>{const e=navigator.userAgent.match(/Firefox[/\s](\d+\.\d+)/);return Array.isArray(e)&&e.length>=2?+e[1]:0})(),d=Boolean(n&&window.document.documentMode),f=!!navigator.sendBeacon},1117:(e,t,r)=>{r.d(t,{w:()=>o});var n=r(50);const i={agentIdentifier:"",ee:void 0};class o{constructor(e){try{if("object"!=typeof e)return(0,n.Z)("shared context requires an object as input");this.sharedContext={},Object.assign(this.sharedContext,i),Object.entries(e).forEach((e=>{let[t,r]=e;Object.keys(i).includes(t)&&(this.sharedContext[t]=r)}))}catch(e){(0,n.Z)("An error occured while setting SharedContext",e)}}}},8e3:(e,t,r)=>{r.d(t,{L:()=>d,R:()=>c});var n=r(2177),i=r(1284),o=r(4322),a=r(3325);const s={};function c(e,t){const r={staged:!1,priority:a.p[t]||0};u(e),s[e].get(t)||s[e].set(t,r)}function u(e){e&&(s[e]||(s[e]=new Map))}function d(){let e=arguments.length>0&&void 0!==arguments[0]?arguments[0]:"",t=arguments.length>1&&void 0!==arguments[1]?arguments[1]:"feature";if(u(e),!e||!s[e].get(t))return a(t);s[e].get(t).staged=!0;const r=[...s[e]];function a(t){const r=e?n.ee.get(e):n.ee,a=o.X.handlers;if(r.backlog&&a){var s=r.backlog[t],c=a[t];if(c){for(var u=0;s&&u {let[t,r]=e;return r.staged}))&&(r.sort(((e,t)=>e[1].priority-t[1].priority)),r.forEach((e=>{let[t]=e;a(t)})))}function f(e,t){var r=e[1];(0,i.D)(t[r],(function(t,r){var n=e[0];if(r[0]===n){var i=r[1],o=e[3],a=e[2];i.apply(o,a)}}))}},2177:(e,t,r)=>{r.d(t,{c:()=>f,ee:()=>u});var n=r(8632),i=r(2210),o=r(1284),a=r(5763),s="nr@context";let c=(0,n.fP)();var u;function d(){}function f(e){return(0,i.X)(e,s,l)}function l(){return new d}function h(){u.aborted=!0,u.backlog={}}c.ee?u=c.ee:(u=function e(t,r){var n={},c={},f={},g=!1;try{g=16===r.length&&(0,a.OP)(r).isolatedBacklog}catch(e){}var p={on:b,addEventListener:b,removeEventListener:y,emit:v,get:x,listeners:w,context:m,buffer:A,abort:h,aborted:!1,isBuffering:E,debugId:r,backlog:g?{}:t&&"object"==typeof t.backlog?t.backlog:{}};return p;function m(e){return e&&e instanceof d?e:e?(0,i.X)(e,s,l):l()}function v(e,r,n,i,o){if(!1!==o&&(o=!0),!u.aborted||i){t&&o&&t.emit(e,r,n);for(var a=m(n),s=w(e),d=s.length,f=0;fn,p:()=>i});var n=r(2177).ee.get("handle");function i(e,t,r,i,o){o?(o.buffer([e],i),o.emit(e,t,r)):(n.buffer([e],i),n.emit(e,t,r))}},4322:(e,t,r)=>{r.d(t,{X:()=>o});var n=r(5546);o.on=a;var i=o.handlers={};function o(e,t,r,o){a(o||n.E,i,e,t,r)}function a(e,t,r,i,o){o||(o="feature"),e||(e=n.E);var a=t[o]=t[o]||{};(a[r]=a[r]||[]).push([e,i])}},3239:(e,t,r)=>{r.d(t,{bP:()=>s,iz:()=>c,m$:()=>a});var n=r(385);let i=!1,o=!1;try{const e={get passive(){return i=!0,!1},get signal(){return o=!0,!1}};n._A.addEventListener("test",null,e),n._A.removeEventListener("test",null,e)}catch(e){}function a(e,t){return i||o?{capture:!!e,passive:i,signal:t}:!!e}function s(e,t){let r=arguments.length>2&&void 0!==arguments[2]&&arguments[2],n=arguments.length>3?arguments[3]:void 0;window.addEventListener(e,t,a(r,n))}function c(e,t){let r=arguments.length>2&&void 0!==arguments[2]&&arguments[2],n=arguments.length>3?arguments[3]:void 0;document.addEventListener(e,t,a(r,n))}},4402:(e,t,r)=>{r.d(t,{Ht:()=>u,M:()=>c,Rl:()=>a,ky:()=>s});var n=r(385);const i="xxxxxxxx-xxxx-4xxx-yxxx-xxxxxxxxxxxx";function o(e,t){return e?15&e[t]:16*Math.random()|0}function a(){const e=n._A?.crypto||n._A?.msCrypto;let t,r=0;return e&&e.getRandomValues&&(t=e.getRandomValues(new Uint8Array(31))),i.split("").map((e=>"x"===e?o(t,++r).toString(16):"y"===e?(3&o()|8).toString(16):e)).join("")}function s(e){const t=n._A?.crypto||n._A?.msCrypto;let r,i=0;t&&t.getRandomValues&&(r=t.getRandomValues(new Uint8Array(31)));const a=[];for(var s=0;s {r.d(t,{Bq:()=>n,Hb:()=>o,oD:()=>i});const n="NRBA",i=144e5,o=18e5},7894:(e,t,r)=>{function n(){return Math.round(performance.now())}r.d(t,{z:()=>n})},7243:(e,t,r)=>{r.d(t,{e:()=>o});var n=r(385),i={};function o(e){if(e in i)return i[e];if(0===(e||"").indexOf("data:"))return{protocol:"data"};let t;var r=n._A?.location,o={};if(n.il)t=document.createElement("a"),t.href=e;else try{t=new URL(e,r.href)}catch(e){return o}o.port=t.port;var a=t.href.split("://");!o.port&&a[1]&&(o.port=a[1].split("/")[0].split("@").pop().split(":")[1]),o.port&&"0"!==o.port||(o.port="https"===a[0]?"443":"80"),o.hostname=t.hostname||r.hostname,o.pathname=t.pathname,o.protocol=a[0],"/"!==o.pathname.charAt(0)&&(o.pathname="/"+o.pathname);var s=!t.protocol||":"===t.protocol||t.protocol===r.protocol,c=t.hostname===r.hostname&&t.port===r.port;return o.sameOrigin=s&&(!t.hostname||c),"/"===o.pathname&&(i[e]=o),o}},50:(e,t,r)=>{function n(e,t){"function"==typeof console.warn&&(console.warn("New Relic: ".concat(e)),t&&console.warn(t))}r.d(t,{Z:()=>n})},2587:(e,t,r)=>{r.d(t,{N:()=>c,T:()=>u});var n=r(2177),i=r(5546),o=r(8e3),a=r(3325);const s={stn:[a.D.sessionTrace],err:[a.D.jserrors,a.D.metrics],ins:[a.D.pageAction],spa:[a.D.spa],sr:[a.D.sessionReplay,a.D.sessionTrace]};function c(e,t){const r=n.ee.get(t);e&&"object"==typeof e&&(Object.entries(e).forEach((e=>{let[t,n]=e;void 0===u[t]&&(s[t]?s[t].forEach((e=>{n?(0,i.p)("feat-"+t,[],void 0,e,r):(0,i.p)("block-"+t,[],void 0,e,r),(0,i.p)("rumresp-"+t,[Boolean(n)],void 0,e,r)})):n&&(0,i.p)("feat-"+t,[],void 0,void 0,r),u[t]=Boolean(n))})),Object.keys(s).forEach((e=>{void 0===u[e]&&(s[e]?.forEach((t=>(0,i.p)("rumresp-"+e,[!1],void 0,t,r))),u[e]=!1)})),(0,o.L)(t,a.D.pageViewEvent))}const u={}},2210:(e,t,r)=>{r.d(t,{X:()=>i});var n=Object.prototype.hasOwnProperty;function i(e,t,r){if(n.call(e,t))return e[t];var i=r();if(Object.defineProperty&&Object.keys)try{return Object.defineProperty(e,t,{value:i,writable:!0,enumerable:!1}),i}catch(e){}return e[t]=i,i}},1284:(e,t,r)=>{r.d(t,{D:()=>n});const n=(e,t)=>Object.entries(e||{}).map((e=>{let[r,n]=e;return t(r,n)}))},4351:(e,t,r)=>{r.d(t,{P:()=>o});var n=r(2177);const i=()=>{const e=new WeakSet;return(t,r)=>{if("object"==typeof r&&null!==r){if(e.has(r))return;e.add(r)}return r}};function o(e){try{return JSON.stringify(e,i())}catch(e){try{n.ee.emit("internal-error",[e])}catch(e){}}}},3960:(e,t,r)=>{r.d(t,{K:()=>a,b:()=>o});var n=r(3239);function i(){return"undefined"==typeof document||"complete"===document.readyState}function o(e,t){if(i())return e();(0,n.bP)("load",e,t)}function a(e){if(i())return e();(0,n.iz)("DOMContentLoaded",e)}},8632:(e,t,r)=>{r.d(t,{EZ:()=>u,Qy:()=>c,ce:()=>o,fP:()=>a,gG:()=>d,mF:()=>s});var n=r(7894),i=r(385);const o={beacon:"bam.nr-data.net",errorBeacon:"bam.nr-data.net"};function a(){return i._A.NREUM||(i._A.NREUM={}),void 0===i._A.newrelic&&(i._A.newrelic=i._A.NREUM),i._A.NREUM}function s(){let e=a();return e.o||(e.o={ST:i._A.setTimeout,SI:i._A.setImmediate,CT:i._A.clearTimeout,XHR:i._A.XMLHttpRequest,REQ:i._A.Request,EV:i._A.Event,PR:i._A.Promise,MO:i._A.MutationObserver,FETCH:i._A.fetch}),e}function c(e,t,r){let i=a();const o=i.initializedAgents||{},s=o[e]||{};return Object.keys(s).length||(s.initializedAt={ms:(0,n.z)(),date:new Date}),i.initializedAgents={...o,[e]:{...s,[r]:t}},i}function u(e,t){a()[e]=t}function d(){return function(){let e=a();const t=e.info||{};e.info={beacon:o.beacon,errorBeacon:o.errorBeacon,...t}}(),function(){let e=a();const t=e.init||{};e.init={...t}}(),s(),function(){let e=a();const t=e.loader_config||{};e.loader_config={...t}}(),a()}},7956:(e,t,r)=>{r.d(t,{N:()=>i});var n=r(3239);function i(e){let t=arguments.length>1&&void 0!==arguments[1]&&arguments[1],r=arguments.length>2?arguments[2]:void 0,i=arguments.length>3?arguments[3]:void 0;return void(0,n.iz)("visibilitychange",(function(){if(t)return void("hidden"==document.visibilityState&&e());e(document.visibilityState)}),r,i)}},1214:(e,t,r)=>{r.d(t,{em:()=>v,u5:()=>N,QU:()=>S,_L:()=>I,Gm:()=>L,Lg:()=>M,gy:()=>U,BV:()=>Q,Kf:()=>ee});var n=r(2177);const i="nr@original";var o=Object.prototype.hasOwnProperty,a=!1;function s(e,t){return e||(e=n.ee),r.inPlace=function(e,t,n,i,o){n||(n="");var a,s,c,u="-"===n.charAt(0);for(c=0;c 2?n-2:0),o=2;o {r(A[T],e,w),r(E[T],e,w)})),r(l._A,"fetch",y),t.on(y+"end",(function(e,r){var n=this;if(r){var i=r.headers.get("content-length");null!==i&&(n.rxSize=i),t.emit(y+"done",[null,r],n)}else t.emit(y+"done",[e],n)})),t}const O={},j=["pushState","replaceState"];function S(e){const t=function(e){return(e||n.ee).get("history")}(e);return!l.il||O[t.debugId]++||(O[t.debugId]=1,s(t).inPlace(window.history,j,"-")),t}var P=r(3239);const C={},R=["appendChild","insertBefore","replaceChild"];function I(e){const t=function(e){return(e||n.ee).get("jsonp")}(e);if(!l.il||C[t.debugId])return t;C[t.debugId]=!0;var r=s(t),i=/[?&](?:callback|cb)=([^&#]+)/,o=/(.*)\.([^.]+)/,a=/^(\w+)(\.|$)(.*)$/;function c(e,t){var r=e.match(a),n=r[1],i=r[3];return i?c(i,t[n]):t[n]}return r.inPlace(Node.prototype,R,"dom-"),t.on("dom-start",(function(e){!function(e){if(!e||"string"!=typeof e.nodeName||"script"!==e.nodeName.toLowerCase())return;if("function"!=typeof e.addEventListener)return;var n=(a=e.src,s=a.match(i),s?s[1]:null);var a,s;if(!n)return;var u=function(e){var t=e.match(o);if(t&&t.length>=3)return{key:t[2],parent:c(t[1],window)};return{key:e,parent:window}}(n);if("function"!=typeof u.parent[u.key])return;var d={};function f(){t.emit("jsonp-end",[],d),e.removeEventListener("load",f,(0,P.m$)(!1)),e.removeEventListener("error",l,(0,P.m$)(!1))}function l(){t.emit("jsonp-error",[],d),t.emit("jsonp-end",[],d),e.removeEventListener("load",f,(0,P.m$)(!1)),e.removeEventListener("error",l,(0,P.m$)(!1))}r.inPlace(u.parent,[u.key],"cb-",d),e.addEventListener("load",f,(0,P.m$)(!1)),e.addEventListener("error",l,(0,P.m$)(!1)),t.emit("new-jsonp",[e.src],d)}(e[0])})),t}var k=r(5763);const H={};function L(e){const t=function(e){return(e||n.ee).get("mutation")}(e);if(!l.il||H[t.debugId])return t;H[t.debugId]=!0;var r=s(t),i=k.Yu.MO;return i&&(window.MutationObserver=function(e){return this instanceof i?new i(r(e,"fn-")):i.apply(this,arguments)},MutationObserver.prototype=i.prototype),t}const z={};function M(e){const t=function(e){return(e||n.ee).get("promise")}(e);if(z[t.debugId])return t;z[t.debugId]=!0;var r=n.c,o=s(t),a=k.Yu.PR;return a&&function(){function e(r){var n=t.context(),i=o(r,"executor-",n,null,!1);const s=Reflect.construct(a,[i],e);return t.context(s).getCtx=function(){return n},s}l._A.Promise=e,Object.defineProperty(e,"name",{value:"Promise"}),e.toString=function(){return a.toString()},Object.setPrototypeOf(e,a),["all","race"].forEach((function(r){const n=a[r];e[r]=function(e){let i=!1;[...e||[]].forEach((e=>{this.resolve(e).then(a("all"===r),a(!1))}));const o=n.apply(this,arguments);return o;function a(e){return function(){t.emit("propagate",[null,!i],o,!1,!1),i=i||!e}}}})),["resolve","reject"].forEach((function(r){const n=a[r];e[r]=function(e){const r=n.apply(this,arguments);return e!==r&&t.emit("propagate",[e,!0],r,!1,!1),r}})),e.prototype=a.prototype;const n=a.prototype.then;a.prototype.then=function(){var e=this,i=r(e);i.promise=e;for(var a=arguments.length,s=new Array(a),c=0;c e())),t};function m(e,t){i.inPlace(t,["onreadystatechange"],"fn-",E)}function b(){var e=this,t=r.context(e);e.readyState>3&&!t.resolved&&(t.resolved=!0,r.emit("xhr-resolved",[],e)),i.inPlace(e,f,"fn-",E)}if(function(e,t){for(var r in e)t[r]=e[r]}(o,p),p.prototype=o.prototype,i.inPlace(p.prototype,J,"-xhr-",E),r.on("send-xhr-start",(function(e,t){m(e,t),function(e){h.push(e),a&&(y?y.then(A):u?u(A):(w=-w,x.data=w))}(t)})),r.on("open-xhr-start",m),a){var y=c&&c.resolve();if(!u&&!c){var w=1,x=document.createTextNode(w);new a(A).observe(x,{characterData:!0})}}else t.on("fn-end",(function(e){e[0]&&e[0].type===d||A()}));function A(){for(var e=0;e {r.d(t,{t:()=>n});const n=r(3325).D.ajax},6660:(e,t,r)=>{r.d(t,{A:()=>i,t:()=>n});const n=r(3325).D.jserrors,i="nr@seenError"},3081:(e,t,r)=>{r.d(t,{gF:()=>o,mY:()=>i,t9:()=>n,vz:()=>s,xS:()=>a});const n=r(3325).D.metrics,i="sm",o="cm",a="storeSupportabilityMetrics",s="storeEventMetrics"},4649:(e,t,r)=>{r.d(t,{t:()=>n});const n=r(3325).D.pageAction},7633:(e,t,r)=>{r.d(t,{Dz:()=>i,OJ:()=>a,qw:()=>o,t9:()=>n});const n=r(3325).D.pageViewEvent,i="firstbyte",o="domcontent",a="windowload"},9251:(e,t,r)=>{r.d(t,{t:()=>n});const n=r(3325).D.pageViewTiming},3614:(e,t,r)=>{r.d(t,{BST_RESOURCE:()=>i,END:()=>s,FEATURE_NAME:()=>n,FN_END:()=>u,FN_START:()=>c,PUSH_STATE:()=>d,RESOURCE:()=>o,START:()=>a});const n=r(3325).D.sessionTrace,i="bstResource",o="resource",a="-start",s="-end",c="fn"+a,u="fn"+s,d="pushState"},7836:(e,t,r)=>{r.d(t,{BODY:()=>A,CB_END:()=>E,CB_START:()=>u,END:()=>x,FEATURE_NAME:()=>i,FETCH:()=>_,FETCH_BODY:()=>v,FETCH_DONE:()=>m,FETCH_START:()=>p,FN_END:()=>c,FN_START:()=>s,INTERACTION:()=>l,INTERACTION_API:()=>d,INTERACTION_EVENTS:()=>o,JSONP_END:()=>b,JSONP_NODE:()=>g,JS_TIME:()=>T,MAX_TIMER_BUDGET:()=>a,REMAINING:()=>f,SPA_NODE:()=>h,START:()=>w,originalSetTimeout:()=>y});var n=r(5763);const i=r(3325).D.spa,o=["click","submit","keypress","keydown","keyup","change"],a=999,s="fn-start",c="fn-end",u="cb-start",d="api-ixn-",f="remaining",l="interaction",h="spaNode",g="jsonpNode",p="fetch-start",m="fetch-done",v="fetch-body-",b="jsonp-end",y=n.Yu.ST,w="-start",x="-end",A="-body",E="cb"+x,T="jsTime",_="fetch"},5938:(e,t,r)=>{r.d(t,{W:()=>o});var n=r(5763),i=r(2177);class o{constructor(e,t,r){this.agentIdentifier=e,this.aggregator=t,this.ee=i.ee.get(e,(0,n.OP)(this.agentIdentifier).isolatedBacklog),this.featureName=r,this.blocked=!1}}},9144:(e,t,r)=>{r.d(t,{j:()=>m});var n=r(3325),i=r(5763),o=r(5546),a=r(2177),s=r(7894),c=r(8e3),u=r(3960),d=r(385),f=r(50),l=r(3081),h=r(8632);function g(){const e=(0,h.gG)();["setErrorHandler","finished","addToTrace","inlineHit","addRelease","addPageAction","setCurrentRouteName","setPageViewName","setCustomAttribute","interaction","noticeError","setUserId"].forEach((t=>{e[t]=function(){for(var r=arguments.length,n=new Array(r),i=0;i 1?r-1:0),i=1;i {e.exposed&&e.api[t]&&o.push(e.api[t](...n))})),o.length>1?o:o[0]}(t,...n)}}))}var p=r(2587);function m(e){let t=arguments.length>1&&void 0!==arguments[1]?arguments[1]:{},m=arguments.length>2?arguments[2]:void 0,v=arguments.length>3?arguments[3]:void 0,{init:b,info:y,loader_config:w,runtime:x={loaderType:m},exposed:A=!0}=t;const E=(0,h.gG)();y||(b=E.init,y=E.info,w=E.loader_config),(0,i.Dg)(e,b||{}),(0,i.GE)(e,w||{}),(0,i.sU)(e,x),y.jsAttributes??={},d.v6&&(y.jsAttributes.isWorker=!0),(0,i.CX)(e,y),g();const T=function(e,t){t||(0,c.R)(e,"api");const h={};var g=a.ee.get(e),p=g.get("tracer"),m="api-",v=m+"ixn-";function b(t,r,n,o){const a=(0,i.C5)(e);return null===r?delete a.jsAttributes[t]:(0,i.CX)(e,{...a,jsAttributes:{...a.jsAttributes,[t]:r}}),x(m,n,!0,o||null===r?"session":void 0)(t,r)}function y(){}["setErrorHandler","finished","addToTrace","inlineHit","addRelease"].forEach((e=>h[e]=x(m,e,!0,"api"))),h.addPageAction=x(m,"addPageAction",!0,n.D.pageAction),h.setCurrentRouteName=x(m,"routeName",!0,n.D.spa),h.setPageViewName=function(t,r){if("string"==typeof t)return"/"!==t.charAt(0)&&(t="/"+t),(0,i.OP)(e).customTransaction=(r||"http://custom.transaction")+t,x(m,"setPageViewName",!0)()},h.setCustomAttribute=function(e,t){let r=arguments.length>2&&void 0!==arguments[2]&&arguments[2];if("string"==typeof e){if(["string","number"].includes(typeof t)||null===t)return b(e,t,"setCustomAttribute",r);(0,f.Z)("Failed to execute setCustomAttribute.\nNon-null value must be a string or number type, but a type of was provided."))}else(0,f.Z)("Failed to execute setCustomAttribute.\nName must be a string type, but a type of was provided."))},h.setUserId=function(e){if("string"==typeof e||null===e)return b("enduser.id",e,"setUserId",!0);(0,f.Z)("Failed to execute setUserId.\nNon-null value must be a string type, but a type of was provided."))},h.interaction=function(){return(new y).get()};var w=y.prototype={createTracer:function(e,t){var r={},i=this,a="function"==typeof t;return(0,o.p)(v+"tracer",[(0,s.z)(),e,r],i,n.D.spa,g),function(){if(p.emit((a?"":"no-")+"fn-start",[(0,s.z)(),i,a],r),a)try{return t.apply(this,arguments)}catch(e){throw p.emit("fn-err",[arguments,this,"string"==typeof e?new Error(e):e],r),e}finally{p.emit("fn-end",[(0,s.z)()],r)}}}};function x(e,t,r,i){return function(){return(0,o.p)(l.xS,["API/"+t+"/called"],void 0,n.D.metrics,g),i&&(0,o.p)(e+t,[(0,s.z)(),...arguments],r?null:this,i,g),r?void 0:this}}function A(){r.e(439).then(r.bind(r,7438)).then((t=>{let{setAPI:r}=t;r(e),(0,c.L)(e,"api")})).catch((()=>(0,f.Z)("Downloading runtime APIs failed...")))}return["actionText","setName","setAttribute","save","ignore","onEnd","getContext","end","get"].forEach((e=>{w[e]=x(v,e,void 0,n.D.spa)})),h.noticeError=function(e,t){"string"==typeof e&&(e=new Error(e)),(0,o.p)(l.xS,["API/noticeError/called"],void 0,n.D.metrics,g),(0,o.p)("err",[e,(0,s.z)(),!1,t],void 0,n.D.jserrors,g)},d.il?(0,u.b)((()=>A()),!0):A(),h}(e,v);return(0,h.Qy)(e,T,"api"),(0,h.Qy)(e,A,"exposed"),(0,h.EZ)("activatedFeatures",p.T),T}},3325:(e,t,r)=>{r.d(t,{D:()=>n,p:()=>i});const n={ajax:"ajax",jserrors:"jserrors",metrics:"metrics",pageAction:"page_action",pageViewEvent:"page_view_event",pageViewTiming:"page_view_timing",sessionReplay:"session_replay",sessionTrace:"session_trace",spa:"spa"},i={[n.pageViewEvent]:1,[n.pageViewTiming]:2,[n.metrics]:3,[n.jserrors]:4,[n.ajax]:5,[n.sessionTrace]:6,[n.pageAction]:7,[n.spa]:8,[n.sessionReplay]:9}}},n={};function i(e){var t=n[e];if(void 0!==t)return t.exports;var o=n[e]={exports:{}};return r[e](o,o.exports,i),o.exports}i.m=r,i.d=(e,t)=>{for(var r in t)i.o(t,r)&&!i.o(e,r)&&Object.defineProperty(e,r,{enumerable:!0,get:t[r]})},i.f={},i.e=e=>Promise.all(Object.keys(i.f).reduce(((t,r)=>(i.f[r](e,t),t)),[])),i.u=e=>(({78:"page_action-aggregate",147:"metrics-aggregate",242:"session-manager",317:"jserrors-aggregate",348:"page_view_timing-aggregate",412:"lazy-feature-loader",439:"async-api",538:"recorder",590:"session_replay-aggregate",675:"compressor",733:"session_trace-aggregate",786:"page_view_event-aggregate",873:"spa-aggregate",898:"ajax-aggregate"}[e]||e)+"."+{78:"ac76d497",147:"3dc53903",148:"1a20d5fe",242:"2a64278a",317:"49e41428",348:"bd6de33a",412:"2f55ce66",439:"30bd804e",538:"1b18459f",590:"cf0efb30",675:"ae9f91a8",733:"83105561",786:"06482edd",860:"03a8b7a5",873:"e6b09d52",898:"998ef92b"}[e]+"-1.236.0.min.js"),i.o=(e,t)=>Object.prototype.hasOwnProperty.call(e,t),e={},t="NRBA:",i.l=(r,n,o,a)=>{if(e[r])e[r].push(n);else{var s,c;if(void 0!==o)for(var u=document.getElementsByTagName("script"),d=0;d {s.onerror=s.onload=null,clearTimeout(h);var i=e[r];if(delete e[r],s.parentNode&&s.parentNode.removeChild(s),i&&i.forEach((e=>e(n))),t)return t(n)},h=setTimeout(l.bind(null,void 0,{type:"timeout",target:s}),12e4);s.onerror=l.bind(null,s.onerror),s.onload=l.bind(null,s.onload),c&&document.head.appendChild(s)}},i.r=e=>{"undefined"!=typeof Symbol&&Symbol.toStringTag&&Object.defineProperty(e,Symbol.toStringTag,{value:"Module"}),Object.defineProperty(e,"__esModule",{value:!0})},i.j=364,i.p="https://js-agent.newrelic.com/",(()=>{var e={364:0,953:0};i.f.j=(t,r)=>{var n=i.o(e,t)?e[t]:void 0;if(0!==n)if(n)r.push(n[2]);else{var o=new Promise(((r,i)=>n=e[t]=[r,i]));r.push(n[2]=o);var a=i.p+i.u(t),s=new Error;i.l(a,(r=>{if(i.o(e,t)&&(0!==(n=e[t])&&(e[t]=void 0),n)){var o=r&&("load"===r.type?"missing":r.type),a=r&&r.target&&r.target.src;s.message="Loading chunk "+t+" failed.\n("+o+": "+a+")",s.name="ChunkLoadError",s.type=o,s.request=a,n[1](s)}}),"chunk-"+t,t)}};var t=(t,r)=>{var n,o,[a,s,c]=r,u=0;if(a.some((t=>0!==e[t]))){for(n in s)i.o(s,n)&&(i.m[n]=s[n]);if(c)c(i)}for(t&&t(r);u {i.r(o);var e=i(3325),t=i(5763);const r=Object.values(e.D);function n(e){const n={};return r.forEach((r=>{n[r]=function(e,r){return!1!==(0,t.Mt)(r,"".concat(e,".enabled"))}(r,e)})),n}var a=i(9144);var s=i(5546),c=i(385),u=i(8e3),d=i(5938),f=i(3960),l=i(50);class h extends d.W{constructor(e,t,r){let n=!(arguments.length>3&&void 0!==arguments[3])||arguments[3];super(e,t,r),this.auto=n,this.abortHandler,this.featAggregate,this.onAggregateImported,n&&(0,u.R)(e,r)}importAggregator(){let e=arguments.length>0&&void 0!==arguments[0]?arguments[0]:{};if(this.featAggregate||!this.auto)return;const r=c.il&&!0===(0,t.Mt)(this.agentIdentifier,"privacy.cookies_enabled");let n;this.onAggregateImported=new Promise((e=>{n=e}));const o=async()=>{let t;try{if(r){const{setupAgentSession:e}=await Promise.all([i.e(860),i.e(242)]).then(i.bind(i,3228));t=e(this.agentIdentifier)}}catch(e){(0,l.Z)("A problem occurred when starting up session manager. This page will not start or extend any session.",e)}try{if(!this.shouldImportAgg(this.featureName,t))return void(0,u.L)(this.agentIdentifier,this.featureName);const{lazyFeatureLoader:r}=await i.e(412).then(i.bind(i,8582)),{Aggregate:o}=await r(this.featureName,"aggregate");this.featAggregate=new o(this.agentIdentifier,this.aggregator,e),n(!0)}catch(e){(0,l.Z)("Downloading and initializing ".concat(this.featureName," failed..."),e),this.abortHandler?.(),n(!1)}};c.il?(0,f.b)((()=>o()),!0):o()}shouldImportAgg(r,n){return r!==e.D.sessionReplay||!1!==(0,t.Mt)(this.agentIdentifier,"session_trace.enabled")&&(!!n?.isNew||!!n?.state.sessionReplay)}}var g=i(7633),p=i(7894);class m extends h{static featureName=g.t9;constructor(r,n){let i=!(arguments.length>2&&void 0!==arguments[2])||arguments[2];if(super(r,n,g.t9,i),("undefined"==typeof PerformanceNavigationTiming||c.Tt)&&"undefined"!=typeof PerformanceTiming){const n=(0,t.OP)(r);n[g.Dz]=Math.max(Date.now()-n.offset,0),(0,f.K)((()=>n[g.qw]=Math.max((0,p.z)()-n[g.Dz],0))),(0,f.b)((()=>{const t=(0,p.z)();n[g.OJ]=Math.max(t-n[g.Dz],0),(0,s.p)("timing",["load",t],void 0,e.D.pageViewTiming,this.ee)}))}this.importAggregator()}}var v=i(1117),b=i(1284);class y extends v.w{constructor(e){super(e),this.aggregatedData={}}store(e,t,r,n,i){var o=this.getBucket(e,t,r,i);return o.metrics=function(e,t){t||(t={count:0});return t.count+=1,(0,b.D)(e,(function(e,r){t[e]=w(r,t[e])})),t}(n,o.metrics),o}merge(e,t,r,n,i){var o=this.getBucket(e,t,n,i);if(o.metrics){var a=o.metrics;a.count+=r.count,(0,b.D)(r,(function(e,t){if("count"!==e){var n=a[e],i=r[e];i&&!i.c?a[e]=w(i.t,n):a[e]=function(e,t){if(!t)return e;t.c||(t=x(t.t));return t.min=Math.min(e.min,t.min),t.max=Math.max(e.max,t.max),t.t+=e.t,t.sos+=e.sos,t.c+=e.c,t}(i,a[e])}}))}else o.metrics=r}storeMetric(e,t,r,n){var i=this.getBucket(e,t,r);return i.stats=w(n,i.stats),i}getBucket(e,t,r,n){this.aggregatedData[e]||(this.aggregatedData[e]={});var i=this.aggregatedData[e][t];return i||(i=this.aggregatedData[e][t]={params:r||{}},n&&(i.custom=n)),i}get(e,t){return t?this.aggregatedData[e]&&this.aggregatedData[e][t]:this.aggregatedData[e]}take(e){for(var t={},r="",n=!1,i=0;i t.max&&(t.max=e),e 2&&void 0!==arguments[2])||arguments[2];super(e,r,j.t,n),c.il&&((0,t.OP)(e).initHidden=Boolean("hidden"===document.visibilityState),(0,N.N)((()=>(0,s.p)("docHidden",[(0,p.z)()],void 0,j.t,this.ee)),!0),(0,O.bP)("pagehide",(()=>(0,s.p)("winPagehide",[(0,p.z)()],void 0,j.t,this.ee))),this.importAggregator())}}var P=i(3081);class C extends h{static featureName=P.t9;constructor(e,t){let r=!(arguments.length>2&&void 0!==arguments[2])||arguments[2];super(e,t,P.t9,r),this.importAggregator()}}var R,I=i(2210),k=i(1214),H=i(2177),L={};try{R=localStorage.getItem("__nr_flags").split(","),console&&"function"==typeof console.log&&(L.console=!0,-1!==R.indexOf("dev")&&(L.dev=!0),-1!==R.indexOf("nr_dev")&&(L.nrDev=!0))}catch(e){}function z(e){try{L.console&&z(e)}catch(e){}}L.nrDev&&H.ee.on("internal-error",(function(e){z(e.stack)})),L.dev&&H.ee.on("fn-err",(function(e,t,r){z(r.stack)})),L.dev&&(z("NR AGENT IN DEVELOPMENT MODE"),z("flags: "+(0,b.D)(L,(function(e,t){return e})).join(", ")));var M=i(6660);class B extends h{static featureName=M.t;constructor(r,n){let i=!(arguments.length>2&&void 0!==arguments[2])||arguments[2];super(r,n,M.t,i),this.skipNext=0;try{this.removeOnAbort=new AbortController}catch(e){}const o=this;o.ee.on("fn-start",(function(e,t,r){o.abortHandler&&(o.skipNext+=1)})),o.ee.on("fn-err",(function(t,r,n){o.abortHandler&&!n[M.A]&&((0,I.X)(n,M.A,(function(){return!0})),this.thrown=!0,(0,s.p)("err",[n,(0,p.z)()],void 0,e.D.jserrors,o.ee))})),o.ee.on("fn-end",(function(){o.abortHandler&&!this.thrown&&o.skipNext>0&&(o.skipNext-=1)})),o.ee.on("internal-error",(function(t){(0,s.p)("ierr",[t,(0,p.z)(),!0],void 0,e.D.jserrors,o.ee)})),this.origOnerror=c._A.onerror,c._A.onerror=this.onerrorHandler.bind(this),c._A.addEventListener("unhandledrejection",(t=>{const r=function(e){let t="Unhandled Promise Rejection: ";if(e instanceof Error)try{return e.message=t+e.message,e}catch(t){return e}if(void 0===e)return new Error(t);try{return new Error(t+(0,D.P)(e))}catch(e){return new Error(t)}}(t.reason);(0,s.p)("err",[r,(0,p.z)(),!1,{unhandledPromiseRejection:1}],void 0,e.D.jserrors,this.ee)}),(0,O.m$)(!1,this.removeOnAbort?.signal)),(0,k.gy)(this.ee),(0,k.BV)(this.ee),(0,k.em)(this.ee),(0,t.OP)(r).xhrWrappable&&(0,k.Kf)(this.ee),this.abortHandler=this.#e,this.importAggregator()}#e(){this.removeOnAbort?.abort(),this.abortHandler=void 0}onerrorHandler(t,r,n,i,o){"function"==typeof this.origOnerror&&this.origOnerror(...arguments);try{this.skipNext?this.skipNext-=1:(0,s.p)("err",[o||new F(t,r,n),(0,p.z)()],void 0,e.D.jserrors,this.ee)}catch(t){try{(0,s.p)("ierr",[t,(0,p.z)(),!0],void 0,e.D.jserrors,this.ee)}catch(e){}}return!1}}function F(e,t,r){this.message=e||"Uncaught error with no additional information",this.sourceURL=t,this.line=r}let U=1;const q="nr@id";function G(e){const t=typeof e;return!e||"object"!==t&&"function"!==t?-1:e===c._A?0:(0,I.X)(e,q,(function(){return U++}))}function V(e){if("string"==typeof e&&e.length)return e.length;if("object"==typeof e){if("undefined"!=typeof ArrayBuffer&&e instanceof ArrayBuffer&&e.byteLength)return e.byteLength;if("undefined"!=typeof Blob&&e instanceof Blob&&e.size)return e.size;if(!("undefined"!=typeof FormData&&e instanceof FormData))try{return(0,D.P)(e).length}catch(e){return}}}var X=i(7243);class W{constructor(e){this.agentIdentifier=e,this.generateTracePayload=this.generateTracePayload.bind(this),this.shouldGenerateTrace=this.shouldGenerateTrace.bind(this)}generateTracePayload(e){if(!this.shouldGenerateTrace(e))return null;var r=(0,t.DL)(this.agentIdentifier);if(!r)return null;var n=(r.accountID||"").toString()||null,i=(r.agentID||"").toString()||null,o=(r.trustKey||"").toString()||null;if(!n||!i)return null;var a=(0,_.M)(),s=(0,_.Ht)(),c=Date.now(),u={spanId:a,traceId:s,timestamp:c};return(e.sameOrigin||this.isAllowedOrigin(e)&&this.useTraceContextHeadersForCors())&&(u.traceContextParentHeader=this.generateTraceContextParentHeader(a,s),u.traceContextStateHeader=this.generateTraceContextStateHeader(a,c,n,i,o)),(e.sameOrigin&&!this.excludeNewrelicHeader()||!e.sameOrigin&&this.isAllowedOrigin(e)&&this.useNewrelicHeaderForCors())&&(u.newrelicHeader=this.generateTraceHeader(a,s,c,n,i,o)),u}generateTraceContextParentHeader(e,t){return"00-"+t+"-"+e+"-01"}generateTraceContextStateHeader(e,t,r,n,i){return i+"@nr=0-1-"+r+"-"+n+"-"+e+"----"+t}generateTraceHeader(e,t,r,n,i,o){if(!("function"==typeof c._A?.btoa))return null;var a={v:[0,1],d:{ty:"Browser",ac:n,ap:i,id:e,tr:t,ti:r}};return o&&n!==o&&(a.d.tk=o),btoa((0,D.P)(a))}shouldGenerateTrace(e){return this.isDtEnabled()&&this.isAllowedOrigin(e)}isAllowedOrigin(e){var r=!1,n={};if((0,t.Mt)(this.agentIdentifier,"distributed_tracing")&&(n=(0,t.P_)(this.agentIdentifier).distributed_tracing),e.sameOrigin)r=!0;else if(n.allowed_origins instanceof Array)for(var i=0;i 2&&void 0!==arguments[2])||arguments[2];super(r,n,Z.t,i),(0,t.OP)(r).xhrWrappable&&(this.dt=new W(r),this.handler=(e,t,r,n)=>(0,s.p)(e,t,r,n,this.ee),(0,k.u5)(this.ee),(0,k.Kf)(this.ee),function(r,n,i,o){function a(e){var t=this;t.totalCbs=0,t.called=0,t.cbTime=0,t.end=E,t.ended=!1,t.xhrGuids={},t.lastSize=null,t.loadCaptureCalled=!1,t.params=this.params||{},t.metrics=this.metrics||{},e.addEventListener("load",(function(r){_(t,e)}),(0,O.m$)(!1)),c.IF||e.addEventListener("progress",(function(e){t.lastSize=e.loaded}),(0,O.m$)(!1))}function s(e){this.params={method:e[0]},T(this,e[1]),this.metrics={}}function u(e,n){var i=(0,t.DL)(r);i.xpid&&this.sameOrigin&&n.setRequestHeader("X-NewRelic-ID",i.xpid);var a=o.generateTracePayload(this.parsedOrigin);if(a){var s=!1;a.newrelicHeader&&(n.setRequestHeader("newrelic",a.newrelicHeader),s=!0),a.traceContextParentHeader&&(n.setRequestHeader("traceparent",a.traceContextParentHeader),a.traceContextStateHeader&&n.setRequestHeader("tracestate",a.traceContextStateHeader),s=!0),s&&(this.dt=a)}}function d(e,t){var r=this.metrics,i=e[0],o=this;if(r&&i){var a=V(i);a&&(r.txSize=a)}this.startTime=(0,p.z)(),this.listener=function(e){try{"abort"!==e.type||o.loadCaptureCalled||(o.params.aborted=!0),("load"!==e.type||o.called===o.totalCbs&&(o.onloadCalled||"function"!=typeof t.onload)&&"function"==typeof o.end)&&o.end(t)}catch(e){try{n.emit("internal-error",[e])}catch(e){}}};for(var s=0;s 1?e[1]=i:e.push(i)}else e[0]&&e[0].headers&&s(e[0].headers,n)&&(this.dt=n);function s(e,t){var r=!1;return t.newrelicHeader&&(e.set("newrelic",t.newrelicHeader),r=!0),t.traceContextParentHeader&&(e.set("traceparent",t.traceContextParentHeader),t.traceContextStateHeader&&e.set("tracestate",t.traceContextStateHeader),r=!0),r}}function x(e,t){this.params={},this.metrics={},this.startTime=(0,p.z)(),this.dt=t,e.length>=1&&(this.target=e[0]),e.length>=2&&(this.opts=e[1]);var r,n=this.opts||{},i=this.target;"string"==typeof i?r=i:"object"==typeof i&&i instanceof Y?r=i.url:c._A?.URL&&"object"==typeof i&&i instanceof URL&&(r=i.href),T(this,r);var o=(""+(i&&i instanceof Y&&i.method||n.method||"GET")).toUpperCase();this.params.method=o,this.txSize=V(n.body)||0}function A(t,r){var n;this.endTime=(0,p.z)(),this.params||(this.params={}),this.params.status=r?r.status:0,"string"==typeof this.rxSize&&this.rxSize.length>0&&(n=+this.rxSize);var o={txSize:this.txSize,rxSize:n,duration:(0,p.z)()-this.startTime};i("xhr",[this.params,o,this.startTime,this.endTime,"fetch"],this,e.D.ajax)}function E(t){var r=this.params,n=this.metrics;if(!this.ended){this.ended=!0;for(var o=0;o 2&&void 0!==arguments[2])||arguments[2];super(e,t,we.t,r),this.importAggregator()}}new class{constructor(e){let t=arguments.length>1&&void 0!==arguments[1]?arguments[1]:(0,_.ky)(16);c._A?(this.agentIdentifier=t,this.sharedAggregator=new y({agentIdentifier:this.agentIdentifier}),this.features={},this.desiredFeatures=new Set(e.features||[]),this.desiredFeatures.add(m),Object.assign(this,(0,a.j)(this.agentIdentifier,e,e.loaderType||"agent")),this.start()):(0,l.Z)("Failed to initial the agent. Could not determine the runtime environment.")}get config(){return{info:(0,t.C5)(this.agentIdentifier),init:(0,t.P_)(this.agentIdentifier),loader_config:(0,t.DL)(this.agentIdentifier),runtime:(0,t.OP)(this.agentIdentifier)}}start(){const t="features";try{const r=n(this.agentIdentifier),i=[...this.desiredFeatures];i.sort(((t,r)=>e.p[t.featureName]-e.p[r.featureName])),i.forEach((t=>{if(r[t.featureName]||t.featureName===e.D.pageViewEvent){const n=function(t){switch(t){case e.D.ajax:return[e.D.jserrors];case e.D.sessionTrace:return[e.D.ajax,e.D.pageViewEvent];case e.D.sessionReplay:return[e.D.sessionTrace];case e.D.pageViewTiming:return[e.D.pageViewEvent];default:return[]}}(t.featureName);n.every((e=>r[e]))||(0,l.Z)("".concat(t.featureName," is enabled but one or more dependent features has been disabled (").concat((0,D.P)(n),"). This may cause unintended consequences or missing data...")),this.features[t.featureName]=new t(this.agentIdentifier,this.sharedAggregator)}})),(0,T.Qy)(this.agentIdentifier,this.features,t)}catch(e){(0,l.Z)("Failed to initialize all enabled instrument classes (agent aborted) -",e);for(const e in this.features)this.features[e].abortHandler?.();const r=(0,T.fP)();return delete r.initializedAgents[this.agentIdentifier]?.api,delete r.initializedAgents[this.agentIdentifier]?.[t],delete this.sharedAggregator,r.ee?.abort(),delete r.ee?.get(this.agentIdentifier),!1}}}({features:[J,m,S,class extends h{static featureName=oe;constructor(t,r){if(super(t,r,oe,!(arguments.length>2&&void 0!==arguments[2])||arguments[2]),!c.il)return;const n=this.ee;let i;(0,k.QU)(n),this.eventsEE=(0,k.em)(n),this.eventsEE.on(se,(function(e,t){this.bstStart=(0,p.z)()})),this.eventsEE.on(ae,(function(t,r){(0,s.p)("bst",[t[0],r,this.bstStart,(0,p.z)()],void 0,e.D.sessionTrace,n)})),n.on(ce+ne,(function(e){this.time=(0,p.z)(),this.startPath=location.pathname+location.hash})),n.on(ce+ie,(function(t){(0,s.p)("bstHist",[location.pathname+location.hash,this.startPath,this.time],void 0,e.D.sessionTrace,n)}));try{i=new PerformanceObserver((t=>{const r=t.getEntries();(0,s.p)(te,[r],void 0,e.D.sessionTrace,n)})),i.observe({type:re,buffered:!0})}catch(e){}this.importAggregator({resourceObserver:i})}},C,xe,B,class extends h{static featureName=de;constructor(e,r){if(super(e,r,de,!(arguments.length>2&&void 0!==arguments[2])||arguments[2]),!c.il)return;if(!(0,t.OP)(e).xhrWrappable)return;try{this.removeOnAbort=new AbortController}catch(e){}let n,i=0;const o=this.ee.get("tracer"),a=(0,k._L)(this.ee),s=(0,k.Lg)(this.ee),u=(0,k.BV)(this.ee),d=(0,k.Kf)(this.ee),f=this.ee.get("events"),l=(0,k.u5)(this.ee),h=(0,k.QU)(this.ee),g=(0,k.Gm)(this.ee);function m(e,t){h.emit("newURL",[""+window.location,t])}function v(){i++,n=window.location.hash,this[ve]=(0,p.z)()}function b(){i--,window.location.hash!==n&&m(0,!0);var e=(0,p.z)();this[pe]=~~this[pe]+e-this[ve],this[ye]=e}function y(e,t){e.on(t,(function(){this[t]=(0,p.z)()}))}this.ee.on(ve,v),s.on(be,v),a.on(be,v),this.ee.on(ye,b),s.on(ge,b),a.on(ge,b),this.ee.buffer([ve,ye,"xhr-resolved"],this.featureName),f.buffer([ve],this.featureName),u.buffer(["setTimeout"+le,"clearTimeout"+fe,ve],this.featureName),d.buffer([ve,"new-xhr","send-xhr"+fe],this.featureName),l.buffer([me+fe,me+"-done",me+he+fe,me+he+le],this.featureName),h.buffer(["newURL"],this.featureName),g.buffer([ve],this.featureName),s.buffer(["propagate",be,ge,"executor-err","resolve"+fe],this.featureName),o.buffer([ve,"no-"+ve],this.featureName),a.buffer(["new-jsonp","cb-start","jsonp-error","jsonp-end"],this.featureName),y(l,me+fe),y(l,me+"-done"),y(a,"new-jsonp"),y(a,"jsonp-end"),y(a,"cb-start"),h.on("pushState-end",m),h.on("replaceState-end",m),window.addEventListener("hashchange",m,(0,O.m$)(!0,this.removeOnAbort?.signal)),window.addEventListener("load",m,(0,O.m$)(!0,this.removeOnAbort?.signal)),window.addEventListener("popstate",(function(){m(0,i>1)}),(0,O.m$)(!0,this.removeOnAbort?.signal)),this.abortHandler=this.#e,this.importAggregator()}#e(){this.removeOnAbort?.abort(),this.abortHandler=void 0}}],loaderType:"spa"})})(),window.NRBA=o})(); window.jQuery || document.write(' ') CKEDITOR_BASEPATH='https://f1000research.com/js/vendor/ckeditor/' window.reactTheme = 'research'; window.MathJax = { CommonHTML: { linebreaks: { automatic: true } }, 'HTML-CSS': { linebreaks: { automatic: true } }, SVG: { linebreaks: { automatic: true } }, AuthorInit: function() { MathJax.Hub.Register.MessageHook('End Process', function () { let timeout = false; // holder for timeout id const delay = 250; // delay after event is "complete" to run callback const reflowMath = function() { const dispFormulas = document.querySelectorAll('.disp-formula.panel'); if (!dispFormulas) { return; } for (const dispFormula of dispFormulas) { const child = dispFormula.querySelector('.MathJax_Preview').nextSibling.firstChild; const isMultiline = MathJax.Hub.getAllJax(dispFormula)[0].root.isMultiline; if (dispFormula.offsetWidth < child.offsetWidth || isMultiline) { MathJax.Hub.Queue(['Rerender', MathJax.Hub, dispFormula]); } } }; window.addEventListener('resize', function() { clearTimeout(timeout); // clear the timeout timeout = setTimeout(reflowMath, delay); // start timing for event "completion" }); }); }, }; if (window.location.hash == '#_=_'){ window.location = window.location.href.split('#')[0] } !function(f,b,e,v,n,t,s){if(f.fbq)return;n=f.fbq=function() {n.callMethod? n.callMethod.apply(n,arguments):n.queue.push(arguments)} ;if(!f._fbq)f._fbq=n; n.push=n;n.loaded=!0;n.version='2.0';n.queue=[];t=b.createElement(e);t.async=!0; t.src=v;s=b.getElementsByTagName(e)[0];s.parentNode.insertBefore(t,s)}(window, document,'script','https://connect.facebook.net/en_US/fbevents.js'); fbq('init', '1641728616063202'); fbq('track', "PixelInitialized", {}); (function(h,o,t,j,a,r){ h.hj=h.hj||function(){(h.hj.q=h.hj.q||[]).push(arguments)}; h._hjSettings={hjid:2318163,hjsv:6}; a=o.getElementsByTagName('head')[0]; r=o.createElement('script');r.async=1; r.src=t+h._hjSettings.hjid+j+h._hjSettings.hjsv; a.appendChild(r); })(window,document,'https://static.hotjar.com/c/hotjar-','.js?sv='); search file_upload Submit your research search menu close search Browse Gateways & Collections How to Publish Submit your Research My Submissions Article Guidelines Article Guidelines (New Versions) Open Data, Software and Code Guidelines Open Data and Accessible Source Materials Guidelines (HSS) Open Data, Software and Code Guidelines (PSE) Prepublication Checks Production Process Posters and Slides Guidelines Document Guidelines Article Processing Charges Peer Review Finding Article Reviewers About How it Works For Reviewers Our Advisors Policies Glossary FAQs For Developers Newsroom Contact My Research Submissions Content and Tracking Alerts My Details Sign In file_upload Submit your research { "@context": "https://schema.org", "@type": "ScholarlyArticle", "mainEntityOfPage": { "@type": "WebPage", "@id": "https://f1000research.com/articles/14-1138" }, "headline": "Mechanisms Associated with PINK1 Mutations in Parkinson's Disease", "datePublished": "2025-10-20T09:14:07", "dateModified": "2026-04-22T12:38:35", "author": [ { "@type": "Person", "name": "Hanliang Dan" }, { "@type": "Person", "name": "Xiaohui Huang" }, { "@type": "Person", "name": "Zheng Liu" }, { "@type": "Person", "name": "Bing Wei" }, { "@type": "Person", "name": "Maslinda Musa" } ], "publisher": { "@type": "Organization", "name": "F1000Research", "logo": { "@type": "ImageObject", "url": "https://f1000research.com/img/AMP/F1000Research_image.png", "height": 480, "width": 60 } }, "image": { "@type": "ImageObject", "url": "https://f1000research.com/img/AMP/F1000Research_image.png", "height": 1200, "width": 150 }, "description": "Abstract Parkinson’s disease (PD) is a widespread and progressively debilitating neurodegenerative disorder, with its global prevalence steadily increasing. Central to its pathogenesis is the PINK1 gene (PTEN-induced putative kinase 1), which plays a pivotal role in mitochondrial function and protecting cells from oxidative stress-induced apoptosis. This review explores the complex relationship between PINK1 mutations and PD, highlighting their involvement in key pathogenic mechanisms. It discusses how these mutations contribute to mitochondrial dysfunction, alterations in phosphorylation pathways, impaired autophagy, and heightened sensitivity to oxidative stress. These insights lay the groundwork for future research and therapeutic approaches, aiming to address the urgent need for effective PD interventions." } { "@context": "http://schema.org", "@type": "BreadcrumbList", "itemListElement": [ { "@type": "ListItem", "position": "1", "item": { "@id": "https://f1000research.com/", "name": "Home" } }, { "@type": "ListItem", "position": "2", "item": { "@id": "https://f1000research.com/browse/articles", "name": "Browse" } }, { "@type": "ListItem", "position": "3", "item": { "@id": "https://f1000research.com/articles/14-1138/v1", "name": "Mechanisms Associated with PINK1 Mutations in Parkinson's Disease" } } ] } Home Browse Mechanisms Associated with PINK1 Mutations in Parkinson's Disease ALL Metrics - Views Downloads Get PDF Get XML Cite How to cite this article Dan H, Huang X, Liu Z et al. Mechanisms Associated with PINK1 Mutations in Parkinson's Disease [version 1; peer review: 1 approved, 1 not approved] . F1000Research 2025, 14 :1138 ( https://doi.org/10.12688/f1000research.170090.1 ) NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article. Close Copy Citation Details Export Export Citation Sciwheel EndNote Ref. Manager Bibtex ProCite Sente EXPORT Select a format first Track Share ▬ ✚ Review Mechanisms Associated with PINK1 Mutations in Parkinson's Disease [version 1; peer review: 1 approved, 1 not approved] Hanliang Dan https://orcid.org/0000-0002-5507-2680 1-3 * , Xiaohui Huang 4 * , Zheng Liu https://orcid.org/0000-0003-4158-6768 4 , Bing Wei 5 , Maslinda Musa 1,2 Hanliang Dan https://orcid.org/0000-0002-5507-2680 1-3 * , Xiaohui Huang 4 * , [...] Zheng Liu https://orcid.org/0000-0003-4158-6768 4 , Bing Wei 5 , Maslinda Musa 1,2 * Equal contributors PUBLISHED 20 Oct 2025 Author details Author details 1 School of Biology, Faculty of Applied Sciences, Universiti Teknologi MARA, UiTM, Shah Alam Seksyen 2, 40450 Selangor, Malaysia 2 Centre for Chemical Synthesis and Polymer Technology, Institute of Science, Universiti Teknologi MARA, UiTM, Shah Alam Seksyen 2, 40450 Selangor, Malaysia 3 Nanxishan Hospital of Guangxi Zhuang Autonomous Region (The Second People's Hospital of Guangxi Zhuang Autonomous Region), Guilin, Guangxi 541002, China 4 Guangxi Key Laboratory of Multimodal Biomarkers and Precision Diagnosis, College of Medical Laboratory and Biotechnology, Guilin Medical University, Guilin, Guangxi, 541004, China 5 Guilin Medical University, Guangxi Key Laboratory of Tumor Immunology and Microenvironment Regulation, Department of Basic Medicine, Guilin, Guangxi 541004, China Hanliang Dan Roles: Investigation, Methodology, Writing – Original Draft Preparation Xiaohui Huang Roles: Investigation, Methodology, Writing – Original Draft Preparation Zheng Liu Roles: Conceptualization, Writing – Original Draft Preparation, Writing – Review & Editing Bing Wei Roles: Conceptualization, Investigation, Writing – Review & Editing Maslinda Musa Roles: Conceptualization, Supervision, Writing – Original Draft Preparation, Writing – Review & Editing OPEN PEER REVIEW DETAILS REVIEWER STATUS This article is included in the Cell & Molecular Biology gateway. This article is included in the Genomics and Genetics gateway. Abstract Abstract Parkinson’s disease (PD) is a widespread and progressively debilitating neurodegenerative disorder, with its global prevalence steadily increasing. Central to its pathogenesis is the PINK1 gene (PTEN-induced putative kinase 1), which plays a pivotal role in mitochondrial function and protecting cells from oxidative stress-induced apoptosis. This review explores the complex relationship between PINK1 mutations and PD, highlighting their involvement in key pathogenic mechanisms. It discusses how these mutations contribute to mitochondrial dysfunction, alterations in phosphorylation pathways, impaired autophagy, and heightened sensitivity to oxidative stress. These insights lay the groundwork for future research and therapeutic approaches, aiming to address the urgent need for effective PD interventions. READ ALL READ LESS Keywords Parkinson's disease, PINK1, genetic mutation, mitochondrial phosphorylation, autophagy pathways, oxidative stress Corresponding Author(s) Zheng Liu ( [email protected] ) Bing Wei ( [email protected] ) Maslinda Musa ( [email protected] ) Close Corresponding authors: Zheng Liu, Bing Wei, Maslinda Musa Competing interests: No competing interests were disclosed. Grant information: The author(s) declared that no grants were involved in supporting this work. Copyright: © 2025 Dan H et al . This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. How to cite: Dan H, Huang X, Liu Z et al. Mechanisms Associated with PINK1 Mutations in Parkinson's Disease [version 1; peer review: 1 approved, 1 not approved] . F1000Research 2025, 14 :1138 ( https://doi.org/10.12688/f1000research.170090.1 ) First published: 20 Oct 2025, 14 :1138 ( https://doi.org/10.12688/f1000research.170090.1 ) Latest published: 22 Apr 2026, 14 :1138 ( https://doi.org/10.12688/f1000research.170090.2 )  There is a newer version of this article available. Suppress this message for one day. 1. Introduction Parkinson’s disease (PD) is a common, chronic, and progressive neurodegenerative disorder, second only to Alzheimer’s disease in prevalence. It affects both the central nervous system and peripheral organs, representing a growing health challenge as the global population ages. According to the World Health Organization’s Parkinson’s Disease Report , more than 8.5 million people were living with PD in 2019, an 81% increase since 2000. During the same period, PD-related deaths doubled to 329,000. A meta-analysis of four North American populations revealed a strong age-related trend in prevalence: less than 1% among men and women aged 45–54 years, increasing to 4% in men and 2% in women aged 85 years and older. 1 The hallmark motor symptoms of PD include tremors, muscle rigidity, bradykinesia, postural instability, and reduced facial expression. The etiology of PD is multifactorial, likely involving interactions between genetic predisposition and environmental exposures. Established environmental risk factors include rural living, agricultural work, well-water consumption, and pesticide exposure. 2 Pathologically, PD is characterized by the degeneration of dopaminergic neurons in the substantia nigra. Within four years of diagnosis, there is a rapid and nearly complete loss of dopaminergic markers in the dorsal striatum, while the loss of melanin-containing neurons in the substantia nigra occurs with a relative delay. 3 PINK1 (PTEN-induced putative kinase 1) mutations represent the second most common cause of autosomal recessive early-onset Parkinson’s disease (EOPD), following Parkin mutations. 4 The PINK1 gene encodes a 581–amino acid protein that is broadly expressed and structurally composed of an N-terminal mitochondrial targeting sequence, a transmembrane domain, and a C-terminal serine/threonine kinase domain. 5 Functionally, PINK1 plays a critical role in protecting cells from oxidative stress–induced apoptosis. Increasing research efforts are directed toward clarifying the biological functions of this serine/threonine kinase, with the goal of informing therapeutic development for PD. 6 The objective of this review is to examine the relationship between PINK1 mutations and Parkinson’s disease, and to elucidate the complex mechanisms involved, thereby providing valuable insights into potential therapeutic strategies. 2. The diversity of PINK1 mutations Mutations in the PINK1 gene are strongly linked to PD. As a mitochondria-associated kinase, PINK1 plays a pivotal role in regulating mitochondrial biogenesis, quality control, and clearance. Loss or dysfunction of PINK1 disrupts these processes, leading to mitochondrial abnormalities characterized by altered morphology, reduced mitochondrial membrane potential (Δψm), and elevated reactive oxygen species (ROS) production, thereby promoting neurodegeneration. Most pathogenic mutations in PINK1 occur within its kinase domain and include nonsense, missense, and deletion variants. 7 In 2004, Valente et al. first identified PINK1 mutations in three consanguineous families of the PARK6 pedigree, reporting two homozygous mutations within the kinase domain: a missense mutation (G309D) and a truncation mutation (W437X). 8 That same year, Hatano et al. identified six novel pathogenic variants (R246X, H271Q, E417G, L347P, and Q239X/R492X) in six unrelated PARK6 families. 9 Subsequent studies further revealed heterozygous mutations in sporadic early-onset PD, highlighting the role of PINK1 in both familial and sporadic disease forms. 10 Expanding research across diverse populations worldwide has identified additional homozygous and heterozygous mutations, many of which are predicted to impair or abolish kinase activity. In vitro analyses confirm that mutations such as G309D, L437P, G386A, and G409V markedly reduce kinase function. 7 , 11 Collectively, these studies provide comprehensive evidence of the close association between PINK1 mutations and PD, underscoring its critical role in early-onset familial and sporadic disease. A deeper understanding of the structural and functional consequences of these mutations has advanced our knowledge of mitochondrial regulation in PD pathogenesis and offers valuable guidance for the development of future therapeutic interventions. 3. PINK1 and the pathogenesis of PD 3.1 PINK1 mutations and mitochondrial phosphorylation Investigating the relationship between PINK1 mutations and phosphorylation pathways offers important insights into the molecular mechanisms underlying PD. Pridgeon et al. demonstrated that PINK1 kinase protects cells against oxidative stress–induced apoptosis by phosphorylating the mitochondrial chaperone TRAP1. However, PD-associated PINK1 mutations (G309D, L347P, and W437X) disrupt this protective mechanism, implicating them in disease pathogenesis. 12 Similarly, Plun-Favreau and colleagues identified PINK1’s interaction with the mitochondrial serine protease HtrA2/OMI. 13 Under physiological conditions, PINK1 activates the p38 pathway, which mediates HtrA2 phosphorylation and enhances its protease activity, thereby conferring resistance to cellular stress. In PD patients carrying PINK1 mutations such as C575R or Y431H, impaired HtrA2 phosphorylation diminishes this protective response, heightening vulnerability to mitochondrial stress. 13 Supporting evidence from Drosophila models confirmed that HtrA2/OMI functions downstream of PINK1 in a shared pathway, although independent of Parkin. 14 , 15 Beyond HtrA2, Parkin itself has been identified as a direct substrate of PINK1. Di Sha et al. showed that PINK1 phosphorylates Parkin, thereby activating its E3 ligase activity, promoting K63-linked polyubiquitination, and enhancing NF-κB–mediated ubiquitin signaling. Notably, pathogenic PINK1 mutations (G309D and L347P) or kinase-inactive PINK1 abrogate this effect, abolishing Parkin phosphorylation and disrupting downstream signaling. 16 Further insights from Drosophila models highlight the essential role of PINK1 autophosphorylation at serine 346 in regulating the PINK1/Parkin pathway. Loss of this phosphorylation event impairs Parkin mitochondrial translocation and activation, ultimately exacerbating photoreceptor neurodegeneration. These findings emphasize the critical role of PINK1 autophosphorylation in mitochondrial quality control and neuronal survival. 17 Collectively, these studies demonstrate how PINK1 mutations compromise key phosphorylation pathways, thereby promoting mitochondrial dysfunction and neurodegeneration ( Figure 1 ). A deeper understanding of these processes not only clarifies PD pathogenesis but also highlights potential targets for therapeutic intervention. Figure 1. Proposed mechanisms by which PINK1 dysfunction contributes to the pathogenesis of Parkinson’s disease. 3.2 PINK1 mutations and abnormal autophagy pathways Mitophagy, the selective removal of damaged mitochondria via autophagosomes, is essential for maintaining mitochondrial quality and regulating mitochondrial number under varying cellular conditions. In Parkinson’s disease, Parkin, an E3 ubiquitin ligase, plays a central role in mitochondrial quality control. 18 Loss of PINK1 function induces mitochondrial fragmentation and defective autophagy, a phenotype that can be rescued by PINK1 re-expression. 19 Under normal conditions, PINK1 undergoes voltage-dependent degradation by the mitochondrial inner membrane rhomboid protease PARL. 20 , 21 However, when mitochondrial membrane potential collapses, PINK1 accumulates on the outer mitochondrial membrane of damaged mitochondria, serving as a signal for their clearance. This accumulated PINK1 recruits Parkin and activates it by phosphorylating ubiquitin at serine 65, establishing ubiquitin as a bona fide PINK1 substrate. 22 Phosphorylated ubiquitin allosterically promotes the release of UBCH7 ubiquitin, relieving Parkin’s autoinhibition and enhancing its E3 ligase activity. 18 , 23 Once translocated to the mitochondrial surface, Parkin ubiquitinates multiple outer mitochondrial membrane (OMM) proteins, facilitating the recruitment of additional factors that initiate mitophagy. 24 In parallel, the ubiquitin-binding adaptor p62 (sequestosome 1) contributes by clustering ubiquitylated proteins through polymerization and recruiting them into autophagosomes via LC3 binding, thereby supporting constitutive basal autophagy. 25 Pathogenic PINK1 mutations disrupt this process by impairing both kinase activity and interaction with Parkin, thereby hindering the selective clearance of depolarized mitochondria and contributing to PD pathogenesis ( Figure 1 ). Geisler et al. demonstrated that PINK1 mutants W437X, Q126P, G309D, and L347P prevent Parkin translocation and block clearance of damaged mitochondria during mitophagy. 26 Interestingly, other studies suggest that these same variants, while impairing Parkin recruitment and kinase activity, may partially correct the aberrant autophagy induced by complete PINK1 deletion. 27 3.3 PINK1 mutations and oxidative stress In 1983, Langston and colleagues reported that several individuals developed Parkinsonian symptoms following intravenous exposure to a banned compound, later identified as 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP), suggesting its potential role as a PD trigger. 28 Structurally analogous to meperidine, MPTP itself is not directly toxic. After crossing the blood–brain barrier (BBB), it is metabolized by astrocytic enzymes into 1-methyl-4-phenyl-2,3-dihydropyridine, which is subsequently oxidized to the toxic metabolite 1-methyl-4-phenylpyridinium (MPP + ) within the central nervous system. 29 , 30 Under normal conditions, electrons pass through mitochondrial respiratory chain complexes (I–IV) to generate ATP, with reactive oxygen species (ROS) produced as byproducts of oxygen metabolism. 31 While ROS are important for immune defense and cell signaling, their overproduction or impaired clearance leads to oxidative stress, which damages DNA, proteins, and lipids. 32 MPP + inhibits mitochondrial NADH dehydrogenase (complex I), resulting in excessive ROS generation and subsequent degeneration of dopaminergic neurons in the nigrostriatal pathway. 33 PINK1 plays a critical protective role in neuronal mitochondria ( Figure 1 ). Human neurons deficient in PINK1 display profound oxidative stress, widespread mitochondrial dysfunction, and abnormal morphology. 34 Deng et al. demonstrated that reduced PINK1 expression via siRNA decreased cell viability and increased susceptibility to MPP + - and rotenone-induced cytotoxicity in SH-SY5Y cells, reinforcing PINK1’s role in dopaminergic neuron survival. 35 Further, Tang et al. identified novel heterozygous missense mutations—DJ-1 A39S and PINK1 P399L—in a Chinese family with early-onset PD. Their findings showed that DJ-1 and PINK1 form a protective complex against oxidative stress, while the disease-associated DJ-1 A39S and PINK1 P399L variants disrupt this interaction, thereby increasing vulnerability to neurotoxin-induced cell death. 36 4. Conclusions In summary, this review highlights the intricate relationship between PINK1 mutations and Parkinson’s disease, emphasizing their effects on mitochondrial function, phosphorylation pathways, autophagy, and oxidative stress. By disrupting mitochondrial quality control, these mutations contribute to the cascade of events leading to neurodegeneration in PD. A deeper understanding of these pathogenic mechanisms not only provides a more comprehensive perspective on disease progression but also lays the groundwork for the development of targeted therapeutic strategies to address the challenges posed by Parkinson’s disease. Data availability No data are associated with this article. References 1. Marras C, Beck JC, Bower JH, et al. : Prevalence of Parkinson’s disease across North America. npj Parkinson’s Disease. 2018; 4 (1): 1–7. Publisher Full Text 2. Kasten M, Chade A, Tanner CM: Epidemiology of Parkinson’s disease. Handb. Clin. Neurol. 2007; 83 : 129–151. PubMed Abstract | Publisher Full Text | Free Full Text 3. Kordower JH, Olanow CW, Dodiya HB, et al. : Disease duration and the integrity of the nigrostriatal system in Parkinson’s disease. Brain. 2013; 136 (8): 2419–2431. PubMed Abstract | Publisher Full Text | Free Full Text 4. Vizziello M, Borellini L, Franco G, et al. : Disruption of Mitochondrial Homeostasis: The Role of PINK1 in Parkinson’s Disease. Cells. 2021; 10 (11): 3022. Publisher Full Text 5. Valente EM, Abou-Sleiman PM, Caputo V, et al. : Hereditary early-onset Parkinson’s disease caused by mutations in PINK1. Science (New York, N.Y.). 2004; 304 (5674): 1158–1160. PubMed Abstract 6. Deas E, Plun-Favreau H, Wood NW: PINK1 function in health and disease. EMBO Mol. Med. 2009; 1 (3): 152–165. PubMed Abstract | Publisher Full Text 7. Sim CH, Lio DSS, Mok SS, et al. : C-terminal truncation and Parkinson’s disease-associated mutations down-regulate the protein serine/threonine kinase activity of PTEN-induced kinase-1. Hum. Mol. Genet. 2006; 15 (21): 3251–3262. PubMed Abstract | Publisher Full Text 8. Valente EM, Abou-Sleiman PM, Caputo V, et al. : Hereditary early-onset Parkinson’s disease caused by mutations in PINK1. Science. 2004; 304 (5674): 1158–1160. PubMed Abstract | Publisher Full Text 9. Hatano Y, Li Y, Sato K, et al. : Novel PINK1 mutations in early-onset parkinsonism. Ann. Neurol. 2004; 56 (3): 424–427. PubMed Abstract 10. Valente EM, Salvi S, Ialongo T, et al. : PINK1 mutations are associated with sporadic early-onset parkinsonism. Ann. Neurol. 2004; 56 (3): 336–341. Publisher Full Text 11. Alexandra B, Marcel V, Deli A, et al. : Mutations in PTEN-induced putative kinase 1 associated with recessive parkinsonism have differential effects on protein stability. Proc. Natl. Acad. Sci. 2005; 102 (16): 5703–5708. 12. Pridgeon JW, Olzmann JA, Chin LS, et al. : PINK1 protects against oxidative stress by phosphorylating mitochondrial chaperone TRAP1. PLoS Biol. 2007; 5 (7): e172. PubMed Abstract | Publisher Full Text | Free Full Text 13. Plun-Favreau H, Klupsch K, Moisoi N, et al. : The mitochondrial protease HtrA2 is regulated by Parkinson’s disease-associated kinase PINK1. Nat. Cell Biol. 2007; 9 (11): 1243–1252. PubMed Abstract | Publisher Full Text 14. Yun J, Cao JH, Dodson MW, et al. : Loss-of-function analysis suggests that Omi/HtrA2 is not an essential component of the PINK1/PARKIN pathway in vivo. J. Neurosci. 2008; 28 (53): 14500–14510. PubMed Abstract | Publisher Full Text 15. Tain LS, Chowdhury RB, Tao RN, et al. : Drosophila HtrA2 is dispensable for apoptosis but acts downstream of PINK1 independently from Parkin. Cell Death Differ. 2009; 16 (8): 1118–1125. PubMed Abstract | Publisher Full Text | Free Full Text 16. Sha D, Chin LS, Li L: Phosphorylation of parkin by Parkinson disease-linked kinase PINK1 activates parkin E3 ligase function and NF-kappaB signaling. Hum. Mol. Genet. 2010; 19 (2): 352–363. PubMed Abstract | Publisher Full Text 17. Zhuang N, Li L, Chen S, et al. : PINK1-dependent phosphorylation of PINK1 and Parkin is essential for mitochondrial quality control. Cell Death Dis. 2016; 7 (12): e2501. PubMed Abstract | Publisher Full Text | Free Full Text 18. Wang XL, Feng ST, Wang ZZ, et al. : Parkin, an E3 Ubiquitin Ligase, Plays an Essential Role in Mitochondrial Quality Control in Parkinson’s Disease. Cell. Mol. Neurobiol. 2021; 41 (7): 1395–1411. PubMed Abstract | Publisher Full Text 19. Dagda RK, Cherra SJ, Kulich SM, et al. : Loss of PINK1 Function Promotes Mitophagy through Effects on Oxidative Stress and Mitochondrial Fission. J. Biol. Chem. 2009; 284 (20): 13843–13855. PubMed Abstract | Publisher Full Text 20. Jin SM, Lazarou M, Wang C, et al. : Mitochondrial membrane potential regulates PINK1 import and proteolytic destabilization by PARL. J. Cell Biol. 2010; 191 (5): 933–942. PubMed Abstract | Publisher Full Text | Free Full Text 21. Matsuda N, Sato S, Shiba K, et al. : PINK1 stabilized by mitochondrial depolarization recruits Parkin to damaged mitochondria and activates latent Parkin for mitophagy. J. Cell Biol. 2010; 189 (2): 211–221. PubMed Abstract | Publisher Full Text 22. Kane LA, Lazarou M, Fogel AI, et al. : PINK1 phosphorylates ubiquitin to activate Parkin E3 ubiquitin ligase activity. J. Cell Biol. 2014; 205 (2): 143–153. PubMed Abstract | Publisher Full Text | Free Full Text 23. Koyano F, Okatsu K, Kosako H, et al. : Ubiquitin is phosphorylated by PINK1 to activate parkin. Nature. 2014; 510 (7503): 162–166. Publisher Full Text 24. Yoshii SR, Kishi C, Ishihara N, et al. : Parkin Mediates Proteasome-dependent Protein Degradation and Rupture of the Outer Mitochondrial Membrane. J. Biol. Chem. 2011; 286 (22): 19630–19640. PubMed Abstract | Publisher Full Text | Free Full Text 25. Pankiv S, Clausen TH, Lamark T, et al. : p62/SQSTM1 binds directly to Atg8/LC3 to facilitate degradation of ubiquitinated protein aggregates by autophagy. J. Biol. Chem. 2007; 282 (33): 24131–24145. PubMed Abstract | Publisher Full Text 26. Geisler S, Holmström KM, Treis A, et al. : The PINK1/Parkin-mediated mitophagy is compromised by PD-associated mutations. Autophagy. 2010; 6 (7): 871–878. PubMed Abstract | Publisher Full Text 27. Gómez-Sánchez R, Yakhine-Diop SMS, Bravo-San Pedro JM, et al. : PINK1 deficiency enhances autophagy and mitophagy induction. Mol. Cell. Oncol. 2016; 3 (2): e1046579. PubMed Abstract | Publisher Full Text 28. Langston JW, Ballard P, Tetrud JW, et al. : Chronic Parkinsonism in humans due to a product of meperidine-analog synthesis. Science. 1983; 219 (4587): 979–980. PubMed Abstract | Publisher Full Text 29. Zeng XS, Geng WS, Jia JJ: Neurotoxin-Induced Animal Models of Parkinson Disease: Pathogenic Mechanism and Assessment. ASN Neuro. 2018; 10 : 1759091418777438. PubMed Abstract | Publisher Full Text | Free Full Text 30. Kato H, Araki T, Imai Y, et al. : Protection of dopaminergic neurons with a novel astrocyte modulating agent (R)-(-)-2-propyloctanoic acid (ONO-2506) in an MPTP-mouse model of Parkinson’s disease. J. Neurol. Sci. 2003; 208 : 9. Publisher Full Text 31. Westermann B: Molecular machinery of mitochondrial fusion and fission. J. Biol. Chem. 2008 May 16; 283 (20): 13501–5. Epub 2008 Mar 27. PubMed Abstract | Publisher Full Text 32. Zhou C, Huang Y, Przedborski S: Oxidative stress in Parkinson’s disease: a mechanism of pathogenic and therapeutic significance. Ann. N. Y. Acad. Sci. 2008 Dec; 1147 : 93–104. PubMed Abstract | Publisher Full Text | Free Full Text 33. Mustapha M, Taib CNM: MPTP-induced mouse model of Parkinson’s disease: A promising direction of therapeutic strategies. Biomolecules and Biomedicine. 2021; 21 (4): 422–433. 34. Wood-Kaczmar A, Gandhi S, Yao Z, et al. : PINK1 Is Necessary for Long Term Survival and Mitochondrial Function in Human Dopaminergic Neurons. PLOS ONE. 2008; 3 (6): e2455. PubMed Abstract | Publisher Full Text | Free Full Text 35. Deng H, Jankovic J, Guo Y, et al. : Small interfering RNA targeting the PINK1 induces apoptosis in dopaminergic cells SH-SY5Y. Biochem. Biophys. Res. Commun. 2005; 337 (4): 1133–1138. PubMed Abstract | Publisher Full Text 36. Tang B, Xiong H, Sun P, et al. : Association of PINK1 and DJ-1 confers digenic inheritance of early-onset Parkinson’s disease. Hum. Mol. Genet. 2006 Jun 1; 15 (11): 1816–1825. PubMed Abstract | Publisher Full Text Comments on this article Comments (0) Version 2 VERSION 2 PUBLISHED 20 Oct 2025 ADD YOUR COMMENT Comment Author details Author details 1 School of Biology, Faculty of Applied Sciences, Universiti Teknologi MARA, UiTM, Shah Alam Seksyen 2, 40450 Selangor, Malaysia 2 Centre for Chemical Synthesis and Polymer Technology, Institute of Science, Universiti Teknologi MARA, UiTM, Shah Alam Seksyen 2, 40450 Selangor, Malaysia 3 Nanxishan Hospital of Guangxi Zhuang Autonomous Region (The Second People's Hospital of Guangxi Zhuang Autonomous Region), Guilin, Guangxi 541002, China 4 Guangxi Key Laboratory of Multimodal Biomarkers and Precision Diagnosis, College of Medical Laboratory and Biotechnology, Guilin Medical University, Guilin, Guangxi, 541004, China 5 Guilin Medical University, Guangxi Key Laboratory of Tumor Immunology and Microenvironment Regulation, Department of Basic Medicine, Guilin, Guangxi 541004, China Hanliang Dan Roles: Investigation, Methodology, Writing – Original Draft Preparation Xiaohui Huang Roles: Investigation, Methodology, Writing – Original Draft Preparation Zheng Liu Roles: Conceptualization, Writing – Original Draft Preparation, Writing – Review & Editing Bing Wei Roles: Conceptualization, Investigation, Writing – Review & Editing Maslinda Musa Roles: Conceptualization, Supervision, Writing – Original Draft Preparation, Writing – Review & Editing Competing interests No competing interests were disclosed. Grant information The author(s) declared that no grants were involved in supporting this work. Article Versions (2) version 2 Revised Published: 22 Apr 2026, 14:1138 https://doi.org/10.12688/f1000research.170090.2 version 1 Published: 20 Oct 2025, 14:1138 https://doi.org/10.12688/f1000research.170090.1 Copyright © 2025 Dan H et al . This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Download Export To Sciwheel Bibtex EndNote ProCite Ref. Manager (RIS) Sente metrics Views Downloads F1000Research - - PubMed Central info_outline Data from PMC are received and updated monthly. - - Citations open_in_new 0 open_in_new 0 open_in_new SEE MORE DETAILS CITE how to cite this article Dan H, Huang X, Liu Z et al. Mechanisms Associated with PINK1 Mutations in Parkinson's Disease [version 1; peer review: 1 approved, 1 not approved] . F1000Research 2025, 14 :1138 ( https://doi.org/10.12688/f1000research.170090.1 ) NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS track receive updates on this article Track an article to receive email alerts on any updates to this article. TRACK THIS ARTICLE Share Open Peer Review Current Reviewer Status: ? Key to Reviewer Statuses VIEW HIDE Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions Version 1 VERSION 1 PUBLISHED 20 Oct 2025 Views 0 Cite How to cite this report: Davis RL. Reviewer Report For: Mechanisms Associated with PINK1 Mutations in Parkinson's Disease [version 1; peer review: 1 approved, 1 not approved] . F1000Research 2025, 14 :1138 ( https://doi.org/10.5256/f1000research.187509.r425648 ) The direct URL for this report is: https://f1000research.com/articles/14-1138/v1#referee-response-425648 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Close Copy Citation Details Reviewer Report 30 Dec 2025 Ryan L Davis , University of Sydney, Sydney, Sydney, Australia Not Approved VIEWS 0 https://doi.org/10.5256/f1000research.187509.r425648 Mechanisms Associated with PINK1 Mutations in Parkinson's Disease ABSTRACT Gene names should be in italics PINK1 and PTEN induced kinase 1 are the HGNC approved symbol and name – perhaps include the stable ... Continue reading READ ALL Mechanisms Associated with PINK1 Mutations in Parkinson's Disease ABSTRACT Gene names should be in italics PINK1 and PTEN induced kinase 1 are the HGNC approved symbol and name – perhaps include the stable ID; HGNC:14581 “Central to its pathogenesis is the PINK1 gene…” is a broad overgeneralisation that makes it seem like PINK1 is the only cause of PD and not more specific to monogenic early-onset familial PD. INTRODUCTION Parkinson’s disease is defined as (PD) in the first line, but the abbreviation is not consistently used thereafter There is a lot of information in the first paragraph that is not appropriately attributed to the original publications. Even a WHO report is mentioned but not referenced. Only the last sentence has an appropriate citation. “ Within four years of diagnosis, there is a rapid and nearly complete loss of dopaminergic markers in the dorsal striatum” neglects the fact that there is a long pro-drome with progressive neurodegeneration. It also reflects the older onset progression of PD and not the early onset monogenic form that is relevant to PINK1. Might need to compare and contrast late vs early onset and idiopathic vs familial. Please check whether ‘variant’ is more appropriate than ‘mutation’ Not sure how appropriate it is to reference a review for core research results. Reference the original citations where possible. Some citations are quite old. Suggest searching for more contemporary research evidencing the claims made. “PINK1 (PTEN-induced putative kinase 1) mutations represent the second most common cause of autosomal recessive early-onset Parkinson’s disease (EOPD), following Parkin mutations” suggests you are talking about the genes, and therefore PINK1 should be in italics and Parkin should be PRKN . 2. DIVERSITY OF PINK1 MUTATIONS “Mutations in the PINK1 gene are strongly linked to PD” is suggestive that this is not definitive but rather remains controversial, which certainly isn’t the case. It would seem that this sentence is perfunctory. First paragraph has no references to support the information presented. Perhaps the second paragraph could be contextualised with the current extent of PINK1 variants and then perhaps that might help address the next comment. If the variants have been known for over 20 years how do they “…offers valuable guidance for the development of future therapeutic interventions.”? I would almost introduce normal PINK1 activity and physiology before talking about variants and how the dysfunction of the molecule underpins pathogenesis. As it stands, we’re learning about variants before really understanding the normal function and mechanisms of PINK1 activitiy. 3. PINK1 AND THE PATHOGENESIS OF PD 3.1 PINK1 MUTATIONS AND MITOCHONDRIAL PHOSPHORYLATION The section title suggests PINK1 phosphorylates mitochondria. Instead, a more accurate section title might be PINK1 mutations and target protein phosphorylation Figure legends should explain a figure as if it were standalone. Figure 1 only has a figure legend title and no supporting description of what is depicted. From author instructions for Reviews: “ Titles and legends: Each figure or table should have a concise title of no more than 15 words. A legend for each figure and table should also be provided that briefly describes the key points and explains any symbols and abbreviations used. The legend should be sufficiently detailed so that the figure or table can stand alone from the main text.” This is currently not the case for Figure 1. 3.2 PINK1 MUTATIONS AND ABNORMAL MITOPHAGY PATHWAYS Parkin is introduced here as if it is the first time it is introduced with its function etc. yet it appears in all sections above While p62 was originally the best characterised autophagy receptor for Parkin-mediated mitophagy, there are several others that have been identified as being more prominent, including optineurin and NDP52. While NBR1 and TAX1BP1 are less prominent like p62. OVERALL Overall I found this short review to provide limited insight into the role of PINK1 in Parkinson’s disease with often outdated or incomplete supporting literature. PINK1 and Parkin have considerable influence outside of mitophagy, for instance PINK1 and Parkin were shown to be central to innate immunity in a knockout model where PD was induced by intestinal infection. Additionally, mitochondrial dysfunction can be the cause or corollary in PD and while this review takes the simplistic and repeated view of PINK1 and Parkin centrality to mitophagy, it is a limited view and negates the peripheral complexities and multifaceted nature of PD pathogenesis. As such, this review does nothing more than to reiterate information that have been presented ad nauseum without opinion or insight into the potential for therapeutic treatment that has thus far failed and remains an endeavour for the entire field. While the review is generally well written it lacks originality in insight and opinion that would drive the field in a particular direction, as a good review should do. As a result, I think this review is severely lacking and adds little to the literature that hasn’t already been presented numerous times previously. Is the topic of the review discussed comprehensively in the context of the current literature? No Are all factual statements correct and adequately supported by citations? Partly Is the review written in accessible language? Yes Are the conclusions drawn appropriate in the context of the current research literature? No Competing Interests: No competing interests were disclosed. Reviewer Expertise: Molecular Pathology, neurogenomics, Parkinson's Disease, Mitochondrial Disease I confirm that I have read this submission and believe that I have an appropriate level of expertise to state that I do not consider it to be of an acceptable scientific standard, for reasons outlined above. Close READ LESS CITE CITE HOW TO CITE THIS REPORT Davis RL. Reviewer Report For: Mechanisms Associated with PINK1 Mutations in Parkinson's Disease [version 1; peer review: 1 approved, 1 not approved] . F1000Research 2025, 14 :1138 ( https://doi.org/10.5256/f1000research.187509.r425648 ) The direct URL for this report is: https://f1000research.com/articles/14-1138/v1#referee-response-425648 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS Report a concern Author Response 22 Apr 2026 Zheng Liu , Guangxi Key Laboratory of Multimodal Biomarkers and Precision Diagnosis, College of Medical Laboratory and Biotechnology, Guilin Medical University, Guilin, 541004, China 22 Apr 2026 Author Response Mechanisms Associated with PINK1 Mutations in Parkinson's Disease ABSTRACT Gene names should be in italics PINK1 and PTEN induced kinase 1 are the HGNC approved symbol and name – perhaps ... Continue reading Mechanisms Associated with PINK1 Mutations in Parkinson's Disease ABSTRACT Gene names should be in italics PINK1 and PTEN induced kinase 1 are the HGNC approved symbol and name – perhaps include the stable ID; HGNC:14581 Respond: In accordance with the reviewer's suggestion, we have italicized all gene names (e.g., PINK1 ) throughout the manuscript to distinguish them from their protein products. Additionally, we have included the HGNC approved symbol, full name, and the stable ID (HGNC:14581) at the first mention of the gene in the Introduction. “Central to its pathogenesis is the PINK1 gene…” is a broad overgeneralisation that makes it seem like PINK1 is the only cause of PD and not more specific to monogenic early-onset familial PD. Respond: We agree with the reviewer that the original statement was too broad. We have revised the text, “While most cases are sporadic, loss-of-function variants in the PINK1 gene are a primary cause of autosomal recessive early-onset PD.”. We have also clarified that studying PINK1 provides a critical window into mitochondrial dysfunction, which is a shared feature in both familial and sporadic PD. INTRODUCTION Parkinson’s disease is defined as (PD) in the first line, but the abbreviation is not consistently used thereafter Respond: We appreciate the reviewer's attention to detail. We have corrected this throughout the manuscript. Following the initial definition in the first sentence of the Introduction, the abbreviation "PD" is now used consistently in place of the full term. There is a lot of information in the first paragraph that is not appropriately attributed to the original publications. Even a WHO report is mentioned but not referenced. Only the last sentence has an appropriate citation. Respond: We apologize for the insufficient citations in the original draft. We have now added the appropriate references for the epidemiological data and specifically cited the World Health Organization (WHO) report on Parkinson’s disease as requested. “Within four years of diagnosis, there is a rapid and nearly complete loss of dopaminergic markers in the dorsal striatum” neglects the fact that there is a long pro-drome with progressive neurodegeneration. It also reflects the older onset progression of PD and not the early onset monogenic form that is relevant to PINK1. Might need to compare and contrast late vs early onset and idiopathic vs familial. Respond: We appreciate this insightful comment. In the revised Introduction (Paragraph 2), we have addressed this by: 1. Acknowledging the prolonged prodromal phase that precedes motor symptoms. 2. Explicitly distinguishing the clinical phenotype of PINK1 -linked PD from idiopathic cases. We now clarify that PINK1 variants are associated with early-onset Parkinsonism (often before age 45) and a sustained response to levodopa, contrasting this with the older-onset progression of sporadic PD as suggested. Please check whether ‘variant’ is more appropriate than ‘mutation’ Respond: We completely agree with the reviewer. In accordance with current genetic nomenclature guidelines, we have globally replaced the term "mutation" with "variant" throughout the manuscript to describe pathogenic genetic alterations. Not sure how appropriate it is to reference a review for core research results. Reference the original citations where possible. Some citations are quite old. Suggest searching for more contemporary research evidencing the claims made. Respond: We appreciate this valid critique. We have comprehensively audited our reference list. We have removed over-reliance on older review articles and replaced them with highly relevant, contemporary primary research articles. “PINK1 (PTEN-induced putative kinase 1) mutations represent the second most common cause of autosomal recessive early-onset Parkinson’s disease (EOPD), following Parkin mutations” suggests you are talking about the genes, and therefore PINK1 should be in italics and Parkin should be PRKN. Respond: PINK1 has been in italics and Parkin has been changed to PRKN. 2. DIVERSITY OF PINK1 MUTATIONS “Mutations in the PINK1 gene are strongly linked to PD” is suggestive that this is not definitive but rather remains controversial, which certainly isn’t the case. It would seem that this sentence is perfunctory. Respond: the sentence has been rewrote. First paragraph has no references to support the information presented. Respond: the references has been added to the first paragraph. Perhaps the second paragraph could be contextualised with the current extent of PINK1 variants and then perhaps that might help address the next comment. Respond: Thank you for the suggestion. I agree that providing a broader context on the current landscape of PINK1 variants—such as the distinction between pathogenic mutations and benign variants, or the known mutation hotspots—would strengthen the paragraph. This additional detail would not only ground the discussion but also serve as a natural bridge to the subsequent point in the comment." If the variants have been known for over 20 years how do they “…offers valuable guidance for the development of future therapeutic interventions.”? Respond: We have extensively revised this section (now Section 3) to address the reviewer's concerns regarding clarity, referencing, and logical flow: 1. Definitive Language: We have removed the tentative phrasing and now explicitly state that pathogenic variants cause a loss of function, disrupting the neuroprotective response. 2. References Added: We have added the necessary citations to the opening paragraph to support the historical identification and structural clustering of these variants [Valente et al., 2004; Scholten et al., 2020]. 3. Updated Context: We have updated the text to reflect the current landscape, noting that over 70 variants have been cataloged, and we have categorized them by mechanism (kinase inactivation vs. protein instability). 4. Removed Outdated Conclusion: We have removed the generic statement about "future therapeutic guidance." Instead, the section now concludes by summarizing the specific pathological outcome of these variants: the failure to sense mitochondrial depolarization and initiate mitophagy. I would almost introduce normal PINK1 activity and physiology before talking about variants and how the dysfunction of the molecule underpins pathogenesis. As it stands, we’re learning about variants before really understanding the normal function and mechanisms of PINK1 activity. Respond: We are grateful for this excellent suggestion. We agree that a solid understanding of the physiological function of PINK1 is a prerequisite for discussing its pathogenicity. In the revised manuscript, we have inserted a new section entitled "Section 2. Physiological Role and Regulation of PINK1" immediately following the Introduction. In this section, we now detail: 1. The canonical import of PINK1 into healthy mitochondria via the TOM/TIM complexes. 2. Its proteolytic processing by MPP and PARL. 3. Its rapid degradation via the N-end rule pathway. 4. Its function as a molecular sensor for mitochondrial membrane potential. This new section provides the necessary biological context before we introduce the pathogenic variants in the subsequent section (now Section 3).3. PINK1 AND THE PATHOGENESIS OF PD 3.1 PINK1 MUTATIONS AND MITOCHONDRIAL PHOSPHORYLATION The section title suggests PINK1 phosphorylates mitochondria. Instead, a more accurate section title might be PINK1 mutations and target protein phosphorylation Respond: We agree with the reviewer that the original title was imprecise. In the revised manuscript, we have renamed this section (now Section 4.1) to " PINK1 Variants Impair Phosphorylation of Downstream Substrates." This title more accurately reflects the mechanistic reality that PINK1 targets specific proteins—namely Parkin and Ubiquitin—rather than the mitochondrial organelle as a whole. Figure legends should explain a figure as if it were standalone. Figure 1 only has a figure legend title and no supporting description of what is depicted. From author instructions for Reviews: “Titles and legends: Each figure or table should have a concise title of no more than 15 words. A legend for each figure and table should also be provided that briefly describes the key points and explains any symbols and abbreviations used. The legend should be sufficiently detailed so that the figure or table can stand alone from the main text.” This is currently not the case for Figure 1. Respond: We apologize for this omission. We have provided a comprehensive, standalone legend for Figure 1 that thoroughly explains the depicted mechanisms, including basal turnover, mitophagy initiation (highlighting OPTN/NDP52), and the disease state. All abbreviations used in the figure are now explicitly defined in the legend. Additionally, we have ensured that Figure 1 is properly cited and integrated within the relevant mechanistic sections of the main text to guide the reader effectively. 3.2 PINK1 MUTATIONS AND ABNORMAL MITOPHAGY PATHWAYS Parkin is introduced here as if it is the first time it is introduced with its function etc. yet it appears in all sections above While p62 was originally the best characterised autophagy receptor for Parkin-mediated mitophagy, there are several others that have been identified as being more prominent, including optineurin and NDP52. While NBR1 and TAX1BP1 are less prominent like p62. Respond: We are grateful to the reviewer for their careful reading and for pointing out this critical evolution in the field. We have made two major revisions to this section (now Section 4.2) to fully address these concerns: 1. Removal of redundant Parkin introduction: We apologize for the redundancy. With the addition of the new "Section 2. Physiological Role and Regulation of PINK1" earlier in the manuscript, Parkin's baseline function is now appropriately introduced upon its first mention. We have carefully revised Section 4.2 to remove the repetitive introduction of Parkin, ensuring a smoother logical flow. 2. Updating the mitophagy receptor consensus: We have significantly revised the text to reflect the current consensus on autophagy receptors. As the reviewer correctly pointed out, we now explicitly state that Optineurin (OPTN) and NDP52 are the primary receptors essential for mitophagy. We also briefly acknowledge that p62, NBR1, and TAX1BP1 play less prominent roles. Furthermore, we now detail how PINK1-mediated phosphorylation of ubiquitin serves as the specific signal to recruit OPTN and NDP52. Key citations have been added to support this updated, contemporary perspective.OVERALL Overall I found this short review to provide limited insight into the role of PINK1 in Parkinson’s disease with often outdated or incomplete supporting literature. PINK1 and Parkin have considerable influence outside of mitophagy, for instance PINK1 and Parkin were shown to be central to innate immunity in a knockout model where PD was induced by intestinal infection. Additionally, mitochondrial dysfunction can be the cause or corollary in PD and while this review takes the simplistic and repeated view of PINK1 and Parkin centrality to mitophagy, it is a limited view and negates the peripheral complexities and multifaceted nature of PD pathogenesis. As such, this review does nothing more than to reiterate information that have been presented ad nauseum without opinion or insight into the potential for therapeutic treatment that has thus far failed and remains an endeavour for the entire field. While the review is generally well written it lacks originality in insight and opinion that would drive the field in a particular direction, as a good review should do. As a result, I think this review is severely lacking and adds little to the literature that hasn’t already been presented numerous times previously. Respond: We are deeply grateful for this profound and constructive critique, which has fundamentally elevated the quality of our manuscript. We fully agree that our previous draft was too narrowly focused on canonical mitophagy and lacked forward-looking translational insights. To address this, we have made substantial additions: 1. Expansion Beyond Mitophagy (Innate Immunity & Gut-Brain Axis): We have added a completely new section (Section 4.3: Beyond Mitophagy: PINK1 and Neuroinflammation). As astutely suggested by the reviewer, we now extensively discuss the role of PINK1 as a critical immunological checkpoint. We specifically highlight the seminal Nature study demonstrating that intestinal infection triggers autoimmune mechanisms in Pink1 -knockout mice via mitochondrial antigen presentation (Matheoud et al., 2019) , as well as the activation of the cGAS-STING pathway. 2. Translational Relevance and Therapeutic Insight: We have added another new section (Section 4.4: Therapeutic Implications) to provide the missing "insight and opinion" on drug development. We critically evaluate novel precision medicine strategies, specifically highlighting the amplification of kinase activity (via Kinetin) and the promising strategy of bypassing mitophagy blockades using USP30 inhibitors. 3. We believe these major revisions transform the manuscript from a mere descriptive summary into a critical, forward-looking review that offers a new framework for understanding PINK1 pathogenesis and developing targeted therapies. Mechanisms Associated with PINK1 Mutations in Parkinson's Disease ABSTRACT Gene names should be in italics PINK1 and PTEN induced kinase 1 are the HGNC approved symbol and name – perhaps include the stable ID; HGNC:14581 Respond: In accordance with the reviewer's suggestion, we have italicized all gene names (e.g., PINK1 ) throughout the manuscript to distinguish them from their protein products. Additionally, we have included the HGNC approved symbol, full name, and the stable ID (HGNC:14581) at the first mention of the gene in the Introduction. “Central to its pathogenesis is the PINK1 gene…” is a broad overgeneralisation that makes it seem like PINK1 is the only cause of PD and not more specific to monogenic early-onset familial PD. Respond: We agree with the reviewer that the original statement was too broad. We have revised the text, “While most cases are sporadic, loss-of-function variants in the PINK1 gene are a primary cause of autosomal recessive early-onset PD.”. We have also clarified that studying PINK1 provides a critical window into mitochondrial dysfunction, which is a shared feature in both familial and sporadic PD. INTRODUCTION Parkinson’s disease is defined as (PD) in the first line, but the abbreviation is not consistently used thereafter Respond: We appreciate the reviewer's attention to detail. We have corrected this throughout the manuscript. Following the initial definition in the first sentence of the Introduction, the abbreviation "PD" is now used consistently in place of the full term. There is a lot of information in the first paragraph that is not appropriately attributed to the original publications. Even a WHO report is mentioned but not referenced. Only the last sentence has an appropriate citation. Respond: We apologize for the insufficient citations in the original draft. We have now added the appropriate references for the epidemiological data and specifically cited the World Health Organization (WHO) report on Parkinson’s disease as requested. “Within four years of diagnosis, there is a rapid and nearly complete loss of dopaminergic markers in the dorsal striatum” neglects the fact that there is a long pro-drome with progressive neurodegeneration. It also reflects the older onset progression of PD and not the early onset monogenic form that is relevant to PINK1. Might need to compare and contrast late vs early onset and idiopathic vs familial. Respond: We appreciate this insightful comment. In the revised Introduction (Paragraph 2), we have addressed this by: 1. Acknowledging the prolonged prodromal phase that precedes motor symptoms. 2. Explicitly distinguishing the clinical phenotype of PINK1 -linked PD from idiopathic cases. We now clarify that PINK1 variants are associated with early-onset Parkinsonism (often before age 45) and a sustained response to levodopa, contrasting this with the older-onset progression of sporadic PD as suggested. Please check whether ‘variant’ is more appropriate than ‘mutation’ Respond: We completely agree with the reviewer. In accordance with current genetic nomenclature guidelines, we have globally replaced the term "mutation" with "variant" throughout the manuscript to describe pathogenic genetic alterations. Not sure how appropriate it is to reference a review for core research results. Reference the original citations where possible. Some citations are quite old. Suggest searching for more contemporary research evidencing the claims made. Respond: We appreciate this valid critique. We have comprehensively audited our reference list. We have removed over-reliance on older review articles and replaced them with highly relevant, contemporary primary research articles. “PINK1 (PTEN-induced putative kinase 1) mutations represent the second most common cause of autosomal recessive early-onset Parkinson’s disease (EOPD), following Parkin mutations” suggests you are talking about the genes, and therefore PINK1 should be in italics and Parkin should be PRKN. Respond: PINK1 has been in italics and Parkin has been changed to PRKN. 2. DIVERSITY OF PINK1 MUTATIONS “Mutations in the PINK1 gene are strongly linked to PD” is suggestive that this is not definitive but rather remains controversial, which certainly isn’t the case. It would seem that this sentence is perfunctory. Respond: the sentence has been rewrote. First paragraph has no references to support the information presented. Respond: the references has been added to the first paragraph. Perhaps the second paragraph could be contextualised with the current extent of PINK1 variants and then perhaps that might help address the next comment. Respond: Thank you for the suggestion. I agree that providing a broader context on the current landscape of PINK1 variants—such as the distinction between pathogenic mutations and benign variants, or the known mutation hotspots—would strengthen the paragraph. This additional detail would not only ground the discussion but also serve as a natural bridge to the subsequent point in the comment." If the variants have been known for over 20 years how do they “…offers valuable guidance for the development of future therapeutic interventions.”? Respond: We have extensively revised this section (now Section 3) to address the reviewer's concerns regarding clarity, referencing, and logical flow: 1. Definitive Language: We have removed the tentative phrasing and now explicitly state that pathogenic variants cause a loss of function, disrupting the neuroprotective response. 2. References Added: We have added the necessary citations to the opening paragraph to support the historical identification and structural clustering of these variants [Valente et al., 2004; Scholten et al., 2020]. 3. Updated Context: We have updated the text to reflect the current landscape, noting that over 70 variants have been cataloged, and we have categorized them by mechanism (kinase inactivation vs. protein instability). 4. Removed Outdated Conclusion: We have removed the generic statement about "future therapeutic guidance." Instead, the section now concludes by summarizing the specific pathological outcome of these variants: the failure to sense mitochondrial depolarization and initiate mitophagy. I would almost introduce normal PINK1 activity and physiology before talking about variants and how the dysfunction of the molecule underpins pathogenesis. As it stands, we’re learning about variants before really understanding the normal function and mechanisms of PINK1 activity. Respond: We are grateful for this excellent suggestion. We agree that a solid understanding of the physiological function of PINK1 is a prerequisite for discussing its pathogenicity. In the revised manuscript, we have inserted a new section entitled "Section 2. Physiological Role and Regulation of PINK1" immediately following the Introduction. In this section, we now detail: 1. The canonical import of PINK1 into healthy mitochondria via the TOM/TIM complexes. 2. Its proteolytic processing by MPP and PARL. 3. Its rapid degradation via the N-end rule pathway. 4. Its function as a molecular sensor for mitochondrial membrane potential. This new section provides the necessary biological context before we introduce the pathogenic variants in the subsequent section (now Section 3).3. PINK1 AND THE PATHOGENESIS OF PD 3.1 PINK1 MUTATIONS AND MITOCHONDRIAL PHOSPHORYLATION The section title suggests PINK1 phosphorylates mitochondria. Instead, a more accurate section title might be PINK1 mutations and target protein phosphorylation Respond: We agree with the reviewer that the original title was imprecise. In the revised manuscript, we have renamed this section (now Section 4.1) to " PINK1 Variants Impair Phosphorylation of Downstream Substrates." This title more accurately reflects the mechanistic reality that PINK1 targets specific proteins—namely Parkin and Ubiquitin—rather than the mitochondrial organelle as a whole. Figure legends should explain a figure as if it were standalone. Figure 1 only has a figure legend title and no supporting description of what is depicted. From author instructions for Reviews: “Titles and legends: Each figure or table should have a concise title of no more than 15 words. A legend for each figure and table should also be provided that briefly describes the key points and explains any symbols and abbreviations used. The legend should be sufficiently detailed so that the figure or table can stand alone from the main text.” This is currently not the case for Figure 1. Respond: We apologize for this omission. We have provided a comprehensive, standalone legend for Figure 1 that thoroughly explains the depicted mechanisms, including basal turnover, mitophagy initiation (highlighting OPTN/NDP52), and the disease state. All abbreviations used in the figure are now explicitly defined in the legend. Additionally, we have ensured that Figure 1 is properly cited and integrated within the relevant mechanistic sections of the main text to guide the reader effectively. 3.2 PINK1 MUTATIONS AND ABNORMAL MITOPHAGY PATHWAYS Parkin is introduced here as if it is the first time it is introduced with its function etc. yet it appears in all sections above While p62 was originally the best characterised autophagy receptor for Parkin-mediated mitophagy, there are several others that have been identified as being more prominent, including optineurin and NDP52. While NBR1 and TAX1BP1 are less prominent like p62. Respond: We are grateful to the reviewer for their careful reading and for pointing out this critical evolution in the field. We have made two major revisions to this section (now Section 4.2) to fully address these concerns: 1. Removal of redundant Parkin introduction: We apologize for the redundancy. With the addition of the new "Section 2. Physiological Role and Regulation of PINK1" earlier in the manuscript, Parkin's baseline function is now appropriately introduced upon its first mention. We have carefully revised Section 4.2 to remove the repetitive introduction of Parkin, ensuring a smoother logical flow. 2. Updating the mitophagy receptor consensus: We have significantly revised the text to reflect the current consensus on autophagy receptors. As the reviewer correctly pointed out, we now explicitly state that Optineurin (OPTN) and NDP52 are the primary receptors essential for mitophagy. We also briefly acknowledge that p62, NBR1, and TAX1BP1 play less prominent roles. Furthermore, we now detail how PINK1-mediated phosphorylation of ubiquitin serves as the specific signal to recruit OPTN and NDP52. Key citations have been added to support this updated, contemporary perspective.OVERALL Overall I found this short review to provide limited insight into the role of PINK1 in Parkinson’s disease with often outdated or incomplete supporting literature. PINK1 and Parkin have considerable influence outside of mitophagy, for instance PINK1 and Parkin were shown to be central to innate immunity in a knockout model where PD was induced by intestinal infection. Additionally, mitochondrial dysfunction can be the cause or corollary in PD and while this review takes the simplistic and repeated view of PINK1 and Parkin centrality to mitophagy, it is a limited view and negates the peripheral complexities and multifaceted nature of PD pathogenesis. As such, this review does nothing more than to reiterate information that have been presented ad nauseum without opinion or insight into the potential for therapeutic treatment that has thus far failed and remains an endeavour for the entire field. While the review is generally well written it lacks originality in insight and opinion that would drive the field in a particular direction, as a good review should do. As a result, I think this review is severely lacking and adds little to the literature that hasn’t already been presented numerous times previously. Respond: We are deeply grateful for this profound and constructive critique, which has fundamentally elevated the quality of our manuscript. We fully agree that our previous draft was too narrowly focused on canonical mitophagy and lacked forward-looking translational insights. To address this, we have made substantial additions: 1. Expansion Beyond Mitophagy (Innate Immunity & Gut-Brain Axis): We have added a completely new section (Section 4.3: Beyond Mitophagy: PINK1 and Neuroinflammation). As astutely suggested by the reviewer, we now extensively discuss the role of PINK1 as a critical immunological checkpoint. We specifically highlight the seminal Nature study demonstrating that intestinal infection triggers autoimmune mechanisms in Pink1 -knockout mice via mitochondrial antigen presentation (Matheoud et al., 2019) , as well as the activation of the cGAS-STING pathway. 2. Translational Relevance and Therapeutic Insight: We have added another new section (Section 4.4: Therapeutic Implications) to provide the missing "insight and opinion" on drug development. We critically evaluate novel precision medicine strategies, specifically highlighting the amplification of kinase activity (via Kinetin) and the promising strategy of bypassing mitophagy blockades using USP30 inhibitors. 3. We believe these major revisions transform the manuscript from a mere descriptive summary into a critical, forward-looking review that offers a new framework for understanding PINK1 pathogenesis and developing targeted therapies. Competing Interests: No competing interests were disclosed. Close Report a concern Respond or Comment COMMENTS ON THIS REPORT Author Response 22 Apr 2026 Zheng Liu , Guangxi Key Laboratory of Multimodal Biomarkers and Precision Diagnosis, College of Medical Laboratory and Biotechnology, Guilin Medical University, Guilin, 541004, China 22 Apr 2026 Author Response Mechanisms Associated with PINK1 Mutations in Parkinson's Disease ABSTRACT Gene names should be in italics PINK1 and PTEN induced kinase 1 are the HGNC approved symbol and name – perhaps ... Continue reading Mechanisms Associated with PINK1 Mutations in Parkinson's Disease ABSTRACT Gene names should be in italics PINK1 and PTEN induced kinase 1 are the HGNC approved symbol and name – perhaps include the stable ID; HGNC:14581 Respond: In accordance with the reviewer's suggestion, we have italicized all gene names (e.g., PINK1 ) throughout the manuscript to distinguish them from their protein products. Additionally, we have included the HGNC approved symbol, full name, and the stable ID (HGNC:14581) at the first mention of the gene in the Introduction. “Central to its pathogenesis is the PINK1 gene…” is a broad overgeneralisation that makes it seem like PINK1 is the only cause of PD and not more specific to monogenic early-onset familial PD. Respond: We agree with the reviewer that the original statement was too broad. We have revised the text, “While most cases are sporadic, loss-of-function variants in the PINK1 gene are a primary cause of autosomal recessive early-onset PD.”. We have also clarified that studying PINK1 provides a critical window into mitochondrial dysfunction, which is a shared feature in both familial and sporadic PD. INTRODUCTION Parkinson’s disease is defined as (PD) in the first line, but the abbreviation is not consistently used thereafter Respond: We appreciate the reviewer's attention to detail. We have corrected this throughout the manuscript. Following the initial definition in the first sentence of the Introduction, the abbreviation "PD" is now used consistently in place of the full term. There is a lot of information in the first paragraph that is not appropriately attributed to the original publications. Even a WHO report is mentioned but not referenced. Only the last sentence has an appropriate citation. Respond: We apologize for the insufficient citations in the original draft. We have now added the appropriate references for the epidemiological data and specifically cited the World Health Organization (WHO) report on Parkinson’s disease as requested. “Within four years of diagnosis, there is a rapid and nearly complete loss of dopaminergic markers in the dorsal striatum” neglects the fact that there is a long pro-drome with progressive neurodegeneration. It also reflects the older onset progression of PD and not the early onset monogenic form that is relevant to PINK1. Might need to compare and contrast late vs early onset and idiopathic vs familial. Respond: We appreciate this insightful comment. In the revised Introduction (Paragraph 2), we have addressed this by: 1. Acknowledging the prolonged prodromal phase that precedes motor symptoms. 2. Explicitly distinguishing the clinical phenotype of PINK1 -linked PD from idiopathic cases. We now clarify that PINK1 variants are associated with early-onset Parkinsonism (often before age 45) and a sustained response to levodopa, contrasting this with the older-onset progression of sporadic PD as suggested. Please check whether ‘variant’ is more appropriate than ‘mutation’ Respond: We completely agree with the reviewer. In accordance with current genetic nomenclature guidelines, we have globally replaced the term "mutation" with "variant" throughout the manuscript to describe pathogenic genetic alterations. Not sure how appropriate it is to reference a review for core research results. Reference the original citations where possible. Some citations are quite old. Suggest searching for more contemporary research evidencing the claims made. Respond: We appreciate this valid critique. We have comprehensively audited our reference list. We have removed over-reliance on older review articles and replaced them with highly relevant, contemporary primary research articles. “PINK1 (PTEN-induced putative kinase 1) mutations represent the second most common cause of autosomal recessive early-onset Parkinson’s disease (EOPD), following Parkin mutations” suggests you are talking about the genes, and therefore PINK1 should be in italics and Parkin should be PRKN. Respond: PINK1 has been in italics and Parkin has been changed to PRKN. 2. DIVERSITY OF PINK1 MUTATIONS “Mutations in the PINK1 gene are strongly linked to PD” is suggestive that this is not definitive but rather remains controversial, which certainly isn’t the case. It would seem that this sentence is perfunctory. Respond: the sentence has been rewrote. First paragraph has no references to support the information presented. Respond: the references has been added to the first paragraph. Perhaps the second paragraph could be contextualised with the current extent of PINK1 variants and then perhaps that might help address the next comment. Respond: Thank you for the suggestion. I agree that providing a broader context on the current landscape of PINK1 variants—such as the distinction between pathogenic mutations and benign variants, or the known mutation hotspots—would strengthen the paragraph. This additional detail would not only ground the discussion but also serve as a natural bridge to the subsequent point in the comment." If the variants have been known for over 20 years how do they “…offers valuable guidance for the development of future therapeutic interventions.”? Respond: We have extensively revised this section (now Section 3) to address the reviewer's concerns regarding clarity, referencing, and logical flow: 1. Definitive Language: We have removed the tentative phrasing and now explicitly state that pathogenic variants cause a loss of function, disrupting the neuroprotective response. 2. References Added: We have added the necessary citations to the opening paragraph to support the historical identification and structural clustering of these variants [Valente et al., 2004; Scholten et al., 2020]. 3. Updated Context: We have updated the text to reflect the current landscape, noting that over 70 variants have been cataloged, and we have categorized them by mechanism (kinase inactivation vs. protein instability). 4. Removed Outdated Conclusion: We have removed the generic statement about "future therapeutic guidance." Instead, the section now concludes by summarizing the specific pathological outcome of these variants: the failure to sense mitochondrial depolarization and initiate mitophagy. I would almost introduce normal PINK1 activity and physiology before talking about variants and how the dysfunction of the molecule underpins pathogenesis. As it stands, we’re learning about variants before really understanding the normal function and mechanisms of PINK1 activity. Respond: We are grateful for this excellent suggestion. We agree that a solid understanding of the physiological function of PINK1 is a prerequisite for discussing its pathogenicity. In the revised manuscript, we have inserted a new section entitled "Section 2. Physiological Role and Regulation of PINK1" immediately following the Introduction. In this section, we now detail: 1. The canonical import of PINK1 into healthy mitochondria via the TOM/TIM complexes. 2. Its proteolytic processing by MPP and PARL. 3. Its rapid degradation via the N-end rule pathway. 4. Its function as a molecular sensor for mitochondrial membrane potential. This new section provides the necessary biological context before we introduce the pathogenic variants in the subsequent section (now Section 3).3. PINK1 AND THE PATHOGENESIS OF PD 3.1 PINK1 MUTATIONS AND MITOCHONDRIAL PHOSPHORYLATION The section title suggests PINK1 phosphorylates mitochondria. Instead, a more accurate section title might be PINK1 mutations and target protein phosphorylation Respond: We agree with the reviewer that the original title was imprecise. In the revised manuscript, we have renamed this section (now Section 4.1) to " PINK1 Variants Impair Phosphorylation of Downstream Substrates." This title more accurately reflects the mechanistic reality that PINK1 targets specific proteins—namely Parkin and Ubiquitin—rather than the mitochondrial organelle as a whole. Figure legends should explain a figure as if it were standalone. Figure 1 only has a figure legend title and no supporting description of what is depicted. From author instructions for Reviews: “Titles and legends: Each figure or table should have a concise title of no more than 15 words. A legend for each figure and table should also be provided that briefly describes the key points and explains any symbols and abbreviations used. The legend should be sufficiently detailed so that the figure or table can stand alone from the main text.” This is currently not the case for Figure 1. Respond: We apologize for this omission. We have provided a comprehensive, standalone legend for Figure 1 that thoroughly explains the depicted mechanisms, including basal turnover, mitophagy initiation (highlighting OPTN/NDP52), and the disease state. All abbreviations used in the figure are now explicitly defined in the legend. Additionally, we have ensured that Figure 1 is properly cited and integrated within the relevant mechanistic sections of the main text to guide the reader effectively. 3.2 PINK1 MUTATIONS AND ABNORMAL MITOPHAGY PATHWAYS Parkin is introduced here as if it is the first time it is introduced with its function etc. yet it appears in all sections above While p62 was originally the best characterised autophagy receptor for Parkin-mediated mitophagy, there are several others that have been identified as being more prominent, including optineurin and NDP52. While NBR1 and TAX1BP1 are less prominent like p62. Respond: We are grateful to the reviewer for their careful reading and for pointing out this critical evolution in the field. We have made two major revisions to this section (now Section 4.2) to fully address these concerns: 1. Removal of redundant Parkin introduction: We apologize for the redundancy. With the addition of the new "Section 2. Physiological Role and Regulation of PINK1" earlier in the manuscript, Parkin's baseline function is now appropriately introduced upon its first mention. We have carefully revised Section 4.2 to remove the repetitive introduction of Parkin, ensuring a smoother logical flow. 2. Updating the mitophagy receptor consensus: We have significantly revised the text to reflect the current consensus on autophagy receptors. As the reviewer correctly pointed out, we now explicitly state that Optineurin (OPTN) and NDP52 are the primary receptors essential for mitophagy. We also briefly acknowledge that p62, NBR1, and TAX1BP1 play less prominent roles. Furthermore, we now detail how PINK1-mediated phosphorylation of ubiquitin serves as the specific signal to recruit OPTN and NDP52. Key citations have been added to support this updated, contemporary perspective.OVERALL Overall I found this short review to provide limited insight into the role of PINK1 in Parkinson’s disease with often outdated or incomplete supporting literature. PINK1 and Parkin have considerable influence outside of mitophagy, for instance PINK1 and Parkin were shown to be central to innate immunity in a knockout model where PD was induced by intestinal infection. Additionally, mitochondrial dysfunction can be the cause or corollary in PD and while this review takes the simplistic and repeated view of PINK1 and Parkin centrality to mitophagy, it is a limited view and negates the peripheral complexities and multifaceted nature of PD pathogenesis. As such, this review does nothing more than to reiterate information that have been presented ad nauseum without opinion or insight into the potential for therapeutic treatment that has thus far failed and remains an endeavour for the entire field. While the review is generally well written it lacks originality in insight and opinion that would drive the field in a particular direction, as a good review should do. As a result, I think this review is severely lacking and adds little to the literature that hasn’t already been presented numerous times previously. Respond: We are deeply grateful for this profound and constructive critique, which has fundamentally elevated the quality of our manuscript. We fully agree that our previous draft was too narrowly focused on canonical mitophagy and lacked forward-looking translational insights. To address this, we have made substantial additions: 1. Expansion Beyond Mitophagy (Innate Immunity & Gut-Brain Axis): We have added a completely new section (Section 4.3: Beyond Mitophagy: PINK1 and Neuroinflammation). As astutely suggested by the reviewer, we now extensively discuss the role of PINK1 as a critical immunological checkpoint. We specifically highlight the seminal Nature study demonstrating that intestinal infection triggers autoimmune mechanisms in Pink1 -knockout mice via mitochondrial antigen presentation (Matheoud et al., 2019) , as well as the activation of the cGAS-STING pathway. 2. Translational Relevance and Therapeutic Insight: We have added another new section (Section 4.4: Therapeutic Implications) to provide the missing "insight and opinion" on drug development. We critically evaluate novel precision medicine strategies, specifically highlighting the amplification of kinase activity (via Kinetin) and the promising strategy of bypassing mitophagy blockades using USP30 inhibitors. 3. We believe these major revisions transform the manuscript from a mere descriptive summary into a critical, forward-looking review that offers a new framework for understanding PINK1 pathogenesis and developing targeted therapies. Mechanisms Associated with PINK1 Mutations in Parkinson's Disease ABSTRACT Gene names should be in italics PINK1 and PTEN induced kinase 1 are the HGNC approved symbol and name – perhaps include the stable ID; HGNC:14581 Respond: In accordance with the reviewer's suggestion, we have italicized all gene names (e.g., PINK1 ) throughout the manuscript to distinguish them from their protein products. Additionally, we have included the HGNC approved symbol, full name, and the stable ID (HGNC:14581) at the first mention of the gene in the Introduction. “Central to its pathogenesis is the PINK1 gene…” is a broad overgeneralisation that makes it seem like PINK1 is the only cause of PD and not more specific to monogenic early-onset familial PD. Respond: We agree with the reviewer that the original statement was too broad. We have revised the text, “While most cases are sporadic, loss-of-function variants in the PINK1 gene are a primary cause of autosomal recessive early-onset PD.”. We have also clarified that studying PINK1 provides a critical window into mitochondrial dysfunction, which is a shared feature in both familial and sporadic PD. INTRODUCTION Parkinson’s disease is defined as (PD) in the first line, but the abbreviation is not consistently used thereafter Respond: We appreciate the reviewer's attention to detail. We have corrected this throughout the manuscript. Following the initial definition in the first sentence of the Introduction, the abbreviation "PD" is now used consistently in place of the full term. There is a lot of information in the first paragraph that is not appropriately attributed to the original publications. Even a WHO report is mentioned but not referenced. Only the last sentence has an appropriate citation. Respond: We apologize for the insufficient citations in the original draft. We have now added the appropriate references for the epidemiological data and specifically cited the World Health Organization (WHO) report on Parkinson’s disease as requested. “Within four years of diagnosis, there is a rapid and nearly complete loss of dopaminergic markers in the dorsal striatum” neglects the fact that there is a long pro-drome with progressive neurodegeneration. It also reflects the older onset progression of PD and not the early onset monogenic form that is relevant to PINK1. Might need to compare and contrast late vs early onset and idiopathic vs familial. Respond: We appreciate this insightful comment. In the revised Introduction (Paragraph 2), we have addressed this by: 1. Acknowledging the prolonged prodromal phase that precedes motor symptoms. 2. Explicitly distinguishing the clinical phenotype of PINK1 -linked PD from idiopathic cases. We now clarify that PINK1 variants are associated with early-onset Parkinsonism (often before age 45) and a sustained response to levodopa, contrasting this with the older-onset progression of sporadic PD as suggested. Please check whether ‘variant’ is more appropriate than ‘mutation’ Respond: We completely agree with the reviewer. In accordance with current genetic nomenclature guidelines, we have globally replaced the term "mutation" with "variant" throughout the manuscript to describe pathogenic genetic alterations. Not sure how appropriate it is to reference a review for core research results. Reference the original citations where possible. Some citations are quite old. Suggest searching for more contemporary research evidencing the claims made. Respond: We appreciate this valid critique. We have comprehensively audited our reference list. We have removed over-reliance on older review articles and replaced them with highly relevant, contemporary primary research articles. “PINK1 (PTEN-induced putative kinase 1) mutations represent the second most common cause of autosomal recessive early-onset Parkinson’s disease (EOPD), following Parkin mutations” suggests you are talking about the genes, and therefore PINK1 should be in italics and Parkin should be PRKN. Respond: PINK1 has been in italics and Parkin has been changed to PRKN. 2. DIVERSITY OF PINK1 MUTATIONS “Mutations in the PINK1 gene are strongly linked to PD” is suggestive that this is not definitive but rather remains controversial, which certainly isn’t the case. It would seem that this sentence is perfunctory. Respond: the sentence has been rewrote. First paragraph has no references to support the information presented. Respond: the references has been added to the first paragraph. Perhaps the second paragraph could be contextualised with the current extent of PINK1 variants and then perhaps that might help address the next comment. Respond: Thank you for the suggestion. I agree that providing a broader context on the current landscape of PINK1 variants—such as the distinction between pathogenic mutations and benign variants, or the known mutation hotspots—would strengthen the paragraph. This additional detail would not only ground the discussion but also serve as a natural bridge to the subsequent point in the comment." If the variants have been known for over 20 years how do they “…offers valuable guidance for the development of future therapeutic interventions.”? Respond: We have extensively revised this section (now Section 3) to address the reviewer's concerns regarding clarity, referencing, and logical flow: 1. Definitive Language: We have removed the tentative phrasing and now explicitly state that pathogenic variants cause a loss of function, disrupting the neuroprotective response. 2. References Added: We have added the necessary citations to the opening paragraph to support the historical identification and structural clustering of these variants [Valente et al., 2004; Scholten et al., 2020]. 3. Updated Context: We have updated the text to reflect the current landscape, noting that over 70 variants have been cataloged, and we have categorized them by mechanism (kinase inactivation vs. protein instability). 4. Removed Outdated Conclusion: We have removed the generic statement about "future therapeutic guidance." Instead, the section now concludes by summarizing the specific pathological outcome of these variants: the failure to sense mitochondrial depolarization and initiate mitophagy. I would almost introduce normal PINK1 activity and physiology before talking about variants and how the dysfunction of the molecule underpins pathogenesis. As it stands, we’re learning about variants before really understanding the normal function and mechanisms of PINK1 activity. Respond: We are grateful for this excellent suggestion. We agree that a solid understanding of the physiological function of PINK1 is a prerequisite for discussing its pathogenicity. In the revised manuscript, we have inserted a new section entitled "Section 2. Physiological Role and Regulation of PINK1" immediately following the Introduction. In this section, we now detail: 1. The canonical import of PINK1 into healthy mitochondria via the TOM/TIM complexes. 2. Its proteolytic processing by MPP and PARL. 3. Its rapid degradation via the N-end rule pathway. 4. Its function as a molecular sensor for mitochondrial membrane potential. This new section provides the necessary biological context before we introduce the pathogenic variants in the subsequent section (now Section 3).3. PINK1 AND THE PATHOGENESIS OF PD 3.1 PINK1 MUTATIONS AND MITOCHONDRIAL PHOSPHORYLATION The section title suggests PINK1 phosphorylates mitochondria. Instead, a more accurate section title might be PINK1 mutations and target protein phosphorylation Respond: We agree with the reviewer that the original title was imprecise. In the revised manuscript, we have renamed this section (now Section 4.1) to " PINK1 Variants Impair Phosphorylation of Downstream Substrates." This title more accurately reflects the mechanistic reality that PINK1 targets specific proteins—namely Parkin and Ubiquitin—rather than the mitochondrial organelle as a whole. Figure legends should explain a figure as if it were standalone. Figure 1 only has a figure legend title and no supporting description of what is depicted. From author instructions for Reviews: “Titles and legends: Each figure or table should have a concise title of no more than 15 words. A legend for each figure and table should also be provided that briefly describes the key points and explains any symbols and abbreviations used. The legend should be sufficiently detailed so that the figure or table can stand alone from the main text.” This is currently not the case for Figure 1. Respond: We apologize for this omission. We have provided a comprehensive, standalone legend for Figure 1 that thoroughly explains the depicted mechanisms, including basal turnover, mitophagy initiation (highlighting OPTN/NDP52), and the disease state. All abbreviations used in the figure are now explicitly defined in the legend. Additionally, we have ensured that Figure 1 is properly cited and integrated within the relevant mechanistic sections of the main text to guide the reader effectively. 3.2 PINK1 MUTATIONS AND ABNORMAL MITOPHAGY PATHWAYS Parkin is introduced here as if it is the first time it is introduced with its function etc. yet it appears in all sections above While p62 was originally the best characterised autophagy receptor for Parkin-mediated mitophagy, there are several others that have been identified as being more prominent, including optineurin and NDP52. While NBR1 and TAX1BP1 are less prominent like p62. Respond: We are grateful to the reviewer for their careful reading and for pointing out this critical evolution in the field. We have made two major revisions to this section (now Section 4.2) to fully address these concerns: 1. Removal of redundant Parkin introduction: We apologize for the redundancy. With the addition of the new "Section 2. Physiological Role and Regulation of PINK1" earlier in the manuscript, Parkin's baseline function is now appropriately introduced upon its first mention. We have carefully revised Section 4.2 to remove the repetitive introduction of Parkin, ensuring a smoother logical flow. 2. Updating the mitophagy receptor consensus: We have significantly revised the text to reflect the current consensus on autophagy receptors. As the reviewer correctly pointed out, we now explicitly state that Optineurin (OPTN) and NDP52 are the primary receptors essential for mitophagy. We also briefly acknowledge that p62, NBR1, and TAX1BP1 play less prominent roles. Furthermore, we now detail how PINK1-mediated phosphorylation of ubiquitin serves as the specific signal to recruit OPTN and NDP52. Key citations have been added to support this updated, contemporary perspective.OVERALL Overall I found this short review to provide limited insight into the role of PINK1 in Parkinson’s disease with often outdated or incomplete supporting literature. PINK1 and Parkin have considerable influence outside of mitophagy, for instance PINK1 and Parkin were shown to be central to innate immunity in a knockout model where PD was induced by intestinal infection. Additionally, mitochondrial dysfunction can be the cause or corollary in PD and while this review takes the simplistic and repeated view of PINK1 and Parkin centrality to mitophagy, it is a limited view and negates the peripheral complexities and multifaceted nature of PD pathogenesis. As such, this review does nothing more than to reiterate information that have been presented ad nauseum without opinion or insight into the potential for therapeutic treatment that has thus far failed and remains an endeavour for the entire field. While the review is generally well written it lacks originality in insight and opinion that would drive the field in a particular direction, as a good review should do. As a result, I think this review is severely lacking and adds little to the literature that hasn’t already been presented numerous times previously. Respond: We are deeply grateful for this profound and constructive critique, which has fundamentally elevated the quality of our manuscript. We fully agree that our previous draft was too narrowly focused on canonical mitophagy and lacked forward-looking translational insights. To address this, we have made substantial additions: 1. Expansion Beyond Mitophagy (Innate Immunity & Gut-Brain Axis): We have added a completely new section (Section 4.3: Beyond Mitophagy: PINK1 and Neuroinflammation). As astutely suggested by the reviewer, we now extensively discuss the role of PINK1 as a critical immunological checkpoint. We specifically highlight the seminal Nature study demonstrating that intestinal infection triggers autoimmune mechanisms in Pink1 -knockout mice via mitochondrial antigen presentation (Matheoud et al., 2019) , as well as the activation of the cGAS-STING pathway. 2. Translational Relevance and Therapeutic Insight: We have added another new section (Section 4.4: Therapeutic Implications) to provide the missing "insight and opinion" on drug development. We critically evaluate novel precision medicine strategies, specifically highlighting the amplification of kinase activity (via Kinetin) and the promising strategy of bypassing mitophagy blockades using USP30 inhibitors. 3. We believe these major revisions transform the manuscript from a mere descriptive summary into a critical, forward-looking review that offers a new framework for understanding PINK1 pathogenesis and developing targeted therapies. Competing Interests: No competing interests were disclosed. Close Report a concern COMMENT ON THIS REPORT Views 0 Cite How to cite this report: Mohamed EE. Reviewer Report For: Mechanisms Associated with PINK1 Mutations in Parkinson's Disease [version 1; peer review: 1 approved, 1 not approved] . F1000Research 2025, 14 :1138 ( https://doi.org/10.5256/f1000research.187509.r440954 ) The direct URL for this report is: https://f1000research.com/articles/14-1138/v1#referee-response-440954 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Close Copy Citation Details Reviewer Report 29 Dec 2025 Eman Ezzeldien Mohamed , Beni-Suef University, Beni-Suef, Egypt Approved VIEWS 0 https://doi.org/10.5256/f1000research.187509.r440954 Reviewer: This manuscript addresses an important topic by reviewing the mechanisms linking PINK1 mutations to Parkinson’s disease. The review is generally well-referenced and provides informative coverage of mitochondrial dysfunction, autophagy, and oxidative stress. 1. The Introduction should more ... Continue reading READ ALL Reviewer: This manuscript addresses an important topic by reviewing the mechanisms linking PINK1 mutations to Parkinson’s disease. The review is generally well-referenced and provides informative coverage of mitochondrial dysfunction, autophagy, and oxidative stress. 1. The Introduction should more clearly define the scope of the review and highlight existing knowledge gaps. Several sections remain largely descriptive, and greater critical analysis of the literature is needed. 2. the Review should better explain the mechanistic reasons behind the reported pathological outcomes. 3. the clinical and translational relevance of PINK1 mutations could be more explicitly addressed. Improving integration between the figure and the main text would also enhance clarity. Is the topic of the review discussed comprehensively in the context of the current literature? Yes Are all factual statements correct and adequately supported by citations? Partly Is the review written in accessible language? Yes Are the conclusions drawn appropriate in the context of the current research literature? Yes Competing Interests: No competing interests were disclosed. Reviewer Expertise: physiology I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. Close READ LESS CITE CITE HOW TO CITE THIS REPORT Mohamed EE. Reviewer Report For: Mechanisms Associated with PINK1 Mutations in Parkinson's Disease [version 1; peer review: 1 approved, 1 not approved] . F1000Research 2025, 14 :1138 ( https://doi.org/10.5256/f1000research.187509.r440954 ) The direct URL for this report is: https://f1000research.com/articles/14-1138/v1#referee-response-440954 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS Report a concern Author Response 22 Apr 2026 Zheng Liu , Guangxi Key Laboratory of Multimodal Biomarkers and Precision Diagnosis, College of Medical Laboratory and Biotechnology, Guilin Medical University, Guilin, 541004, China 22 Apr 2026 Author Response This manuscript addresses an important topic by reviewing the mechanisms linking PINK1 mutations to Parkinson’s disease. The review is generally well-referenced and provides informative coverage of mitochondrial dysfunction, autophagy, and ... Continue reading This manuscript addresses an important topic by reviewing the mechanisms linking PINK1 mutations to Parkinson’s disease. The review is generally well-referenced and provides informative coverage of mitochondrial dysfunction, autophagy, and oxidative stress. 1. The Introduction should more clearly define the scope of the review and highlight existing knowledge gaps. Several sections remain largely descriptive, and greater critical analysis of the literature is needed. Respond: We agree. We revised the Introduction's final paragraph to clearly define the review's scope and highlight knowledge gaps, specifically PINK1's non-mitophagic roles in innate immunity. We also cited seminal studies on the gut-brain axis and inflammation, such as Matheoud et al. (2019), to enhance our critical analysis. 2. the Review should better explain the mechanistic reasons behind the reported pathological outcomes. Respond: Thank you for the suggestion. We significantly deepened the mechanistic discussions. In Section 3, we detail how specific variants fail to phosphorylate Ubiquitin/Parkin at Ser65. In Section 4.2, we explain how this failure blocks the recruitment of key autophagy receptors (OPTN and NDP52), leading to the accumulation of ROS-producing mitochondria that mechanically drives neurodegeneration. 3. the clinical and translational relevance of PINK1 mutations could be more explicitly addressed. Improving integration between the figure and the main text would also enhance clarity. Respond: We appreciate these suggestions and made two major updates: 1.Translational Relevance: We added a new section (Section 4.4: Therapeutic Implications) exploring precision medicine strategies, highlighting neo-substrates (e.g., Kinetin) and USP30 inhibitors. 2. Figure Integration: We rewrote the legend for Figure 1 so it fully explains the mechanisms and stands alone. We also improved its integration by citing it at key mechanistic junctures (e.g., Sections 2 and 4.2) in the main text. This manuscript addresses an important topic by reviewing the mechanisms linking PINK1 mutations to Parkinson’s disease. The review is generally well-referenced and provides informative coverage of mitochondrial dysfunction, autophagy, and oxidative stress. 1. The Introduction should more clearly define the scope of the review and highlight existing knowledge gaps. Several sections remain largely descriptive, and greater critical analysis of the literature is needed. Respond: We agree. We revised the Introduction's final paragraph to clearly define the review's scope and highlight knowledge gaps, specifically PINK1's non-mitophagic roles in innate immunity. We also cited seminal studies on the gut-brain axis and inflammation, such as Matheoud et al. (2019), to enhance our critical analysis. 2. the Review should better explain the mechanistic reasons behind the reported pathological outcomes. Respond: Thank you for the suggestion. We significantly deepened the mechanistic discussions. In Section 3, we detail how specific variants fail to phosphorylate Ubiquitin/Parkin at Ser65. In Section 4.2, we explain how this failure blocks the recruitment of key autophagy receptors (OPTN and NDP52), leading to the accumulation of ROS-producing mitochondria that mechanically drives neurodegeneration. 3. the clinical and translational relevance of PINK1 mutations could be more explicitly addressed. Improving integration between the figure and the main text would also enhance clarity. Respond: We appreciate these suggestions and made two major updates: 1.Translational Relevance: We added a new section (Section 4.4: Therapeutic Implications) exploring precision medicine strategies, highlighting neo-substrates (e.g., Kinetin) and USP30 inhibitors. 2. Figure Integration: We rewrote the legend for Figure 1 so it fully explains the mechanisms and stands alone. We also improved its integration by citing it at key mechanistic junctures (e.g., Sections 2 and 4.2) in the main text. Competing Interests: None. Close Report a concern Respond or Comment COMMENTS ON THIS REPORT Author Response 22 Apr 2026 Zheng Liu , Guangxi Key Laboratory of Multimodal Biomarkers and Precision Diagnosis, College of Medical Laboratory and Biotechnology, Guilin Medical University, Guilin, 541004, China 22 Apr 2026 Author Response This manuscript addresses an important topic by reviewing the mechanisms linking PINK1 mutations to Parkinson’s disease. The review is generally well-referenced and provides informative coverage of mitochondrial dysfunction, autophagy, and ... Continue reading This manuscript addresses an important topic by reviewing the mechanisms linking PINK1 mutations to Parkinson’s disease. The review is generally well-referenced and provides informative coverage of mitochondrial dysfunction, autophagy, and oxidative stress. 1. The Introduction should more clearly define the scope of the review and highlight existing knowledge gaps. Several sections remain largely descriptive, and greater critical analysis of the literature is needed. Respond: We agree. We revised the Introduction's final paragraph to clearly define the review's scope and highlight knowledge gaps, specifically PINK1's non-mitophagic roles in innate immunity. We also cited seminal studies on the gut-brain axis and inflammation, such as Matheoud et al. (2019), to enhance our critical analysis. 2. the Review should better explain the mechanistic reasons behind the reported pathological outcomes. Respond: Thank you for the suggestion. We significantly deepened the mechanistic discussions. In Section 3, we detail how specific variants fail to phosphorylate Ubiquitin/Parkin at Ser65. In Section 4.2, we explain how this failure blocks the recruitment of key autophagy receptors (OPTN and NDP52), leading to the accumulation of ROS-producing mitochondria that mechanically drives neurodegeneration. 3. the clinical and translational relevance of PINK1 mutations could be more explicitly addressed. Improving integration between the figure and the main text would also enhance clarity. Respond: We appreciate these suggestions and made two major updates: 1.Translational Relevance: We added a new section (Section 4.4: Therapeutic Implications) exploring precision medicine strategies, highlighting neo-substrates (e.g., Kinetin) and USP30 inhibitors. 2. Figure Integration: We rewrote the legend for Figure 1 so it fully explains the mechanisms and stands alone. We also improved its integration by citing it at key mechanistic junctures (e.g., Sections 2 and 4.2) in the main text. This manuscript addresses an important topic by reviewing the mechanisms linking PINK1 mutations to Parkinson’s disease. The review is generally well-referenced and provides informative coverage of mitochondrial dysfunction, autophagy, and oxidative stress. 1. The Introduction should more clearly define the scope of the review and highlight existing knowledge gaps. Several sections remain largely descriptive, and greater critical analysis of the literature is needed. Respond: We agree. We revised the Introduction's final paragraph to clearly define the review's scope and highlight knowledge gaps, specifically PINK1's non-mitophagic roles in innate immunity. We also cited seminal studies on the gut-brain axis and inflammation, such as Matheoud et al. (2019), to enhance our critical analysis. 2. the Review should better explain the mechanistic reasons behind the reported pathological outcomes. Respond: Thank you for the suggestion. We significantly deepened the mechanistic discussions. In Section 3, we detail how specific variants fail to phosphorylate Ubiquitin/Parkin at Ser65. In Section 4.2, we explain how this failure blocks the recruitment of key autophagy receptors (OPTN and NDP52), leading to the accumulation of ROS-producing mitochondria that mechanically drives neurodegeneration. 3. the clinical and translational relevance of PINK1 mutations could be more explicitly addressed. Improving integration between the figure and the main text would also enhance clarity. Respond: We appreciate these suggestions and made two major updates: 1.Translational Relevance: We added a new section (Section 4.4: Therapeutic Implications) exploring precision medicine strategies, highlighting neo-substrates (e.g., Kinetin) and USP30 inhibitors. 2. Figure Integration: We rewrote the legend for Figure 1 so it fully explains the mechanisms and stands alone. We also improved its integration by citing it at key mechanistic junctures (e.g., Sections 2 and 4.2) in the main text. Competing Interests: None. Close Report a concern COMMENT ON THIS REPORT Comments on this article Comments (0) Version 2 VERSION 2 PUBLISHED 20 Oct 2025 ADD YOUR COMMENT Comment keyboard_arrow_left keyboard_arrow_right Open Peer Review Reviewer Status info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions Reviewer Reports Invited Reviewers 1 2 Version 2 (revision) 22 Apr 26 Version 1 20 Oct 25 read read Eman Ezzeldien Mohamed , Beni-Suef University, Beni-Suef, Egypt Ryan L Davis , University of Sydney, Sydney, Australia Comments on this article All Comments (0) Add a comment Sign up for content alerts Sign Up You are now signed up to receive this alert Browse by related subjects keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2026 Davis R. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 30 Dec 2025 | for Version 1 Ryan L Davis , University of Sydney, Sydney, Sydney, Australia 0 Views copyright © 2026 Davis R. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. format_quote Cite this report speaker_notes Responses (1) Not Approved info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions Mechanisms Associated with PINK1 Mutations in Parkinson's Disease ABSTRACT Gene names should be in italics PINK1 and PTEN induced kinase 1 are the HGNC approved symbol and name – perhaps include the stable ID; HGNC:14581 “Central to its pathogenesis is the PINK1 gene…” is a broad overgeneralisation that makes it seem like PINK1 is the only cause of PD and not more specific to monogenic early-onset familial PD. INTRODUCTION Parkinson’s disease is defined as (PD) in the first line, but the abbreviation is not consistently used thereafter There is a lot of information in the first paragraph that is not appropriately attributed to the original publications. Even a WHO report is mentioned but not referenced. Only the last sentence has an appropriate citation. “ Within four years of diagnosis, there is a rapid and nearly complete loss of dopaminergic markers in the dorsal striatum” neglects the fact that there is a long pro-drome with progressive neurodegeneration. It also reflects the older onset progression of PD and not the early onset monogenic form that is relevant to PINK1. Might need to compare and contrast late vs early onset and idiopathic vs familial. Please check whether ‘variant’ is more appropriate than ‘mutation’ Not sure how appropriate it is to reference a review for core research results. Reference the original citations where possible. Some citations are quite old. Suggest searching for more contemporary research evidencing the claims made. “PINK1 (PTEN-induced putative kinase 1) mutations represent the second most common cause of autosomal recessive early-onset Parkinson’s disease (EOPD), following Parkin mutations” suggests you are talking about the genes, and therefore PINK1 should be in italics and Parkin should be PRKN . 2. DIVERSITY OF PINK1 MUTATIONS “Mutations in the PINK1 gene are strongly linked to PD” is suggestive that this is not definitive but rather remains controversial, which certainly isn’t the case. It would seem that this sentence is perfunctory. First paragraph has no references to support the information presented. Perhaps the second paragraph could be contextualised with the current extent of PINK1 variants and then perhaps that might help address the next comment. If the variants have been known for over 20 years how do they “…offers valuable guidance for the development of future therapeutic interventions.”? I would almost introduce normal PINK1 activity and physiology before talking about variants and how the dysfunction of the molecule underpins pathogenesis. As it stands, we’re learning about variants before really understanding the normal function and mechanisms of PINK1 activitiy. 3. PINK1 AND THE PATHOGENESIS OF PD 3.1 PINK1 MUTATIONS AND MITOCHONDRIAL PHOSPHORYLATION The section title suggests PINK1 phosphorylates mitochondria. Instead, a more accurate section title might be PINK1 mutations and target protein phosphorylation Figure legends should explain a figure as if it were standalone. Figure 1 only has a figure legend title and no supporting description of what is depicted. From author instructions for Reviews: “ Titles and legends: Each figure or table should have a concise title of no more than 15 words. A legend for each figure and table should also be provided that briefly describes the key points and explains any symbols and abbreviations used. The legend should be sufficiently detailed so that the figure or table can stand alone from the main text.” This is currently not the case for Figure 1. 3.2 PINK1 MUTATIONS AND ABNORMAL MITOPHAGY PATHWAYS Parkin is introduced here as if it is the first time it is introduced with its function etc. yet it appears in all sections above While p62 was originally the best characterised autophagy receptor for Parkin-mediated mitophagy, there are several others that have been identified as being more prominent, including optineurin and NDP52. While NBR1 and TAX1BP1 are less prominent like p62. OVERALL Overall I found this short review to provide limited insight into the role of PINK1 in Parkinson’s disease with often outdated or incomplete supporting literature. PINK1 and Parkin have considerable influence outside of mitophagy, for instance PINK1 and Parkin were shown to be central to innate immunity in a knockout model where PD was induced by intestinal infection. Additionally, mitochondrial dysfunction can be the cause or corollary in PD and while this review takes the simplistic and repeated view of PINK1 and Parkin centrality to mitophagy, it is a limited view and negates the peripheral complexities and multifaceted nature of PD pathogenesis. As such, this review does nothing more than to reiterate information that have been presented ad nauseum without opinion or insight into the potential for therapeutic treatment that has thus far failed and remains an endeavour for the entire field. While the review is generally well written it lacks originality in insight and opinion that would drive the field in a particular direction, as a good review should do. As a result, I think this review is severely lacking and adds little to the literature that hasn’t already been presented numerous times previously. Is the topic of the review discussed comprehensively in the context of the current literature? No Are all factual statements correct and adequately supported by citations? Partly Is the review written in accessible language? Yes Are the conclusions drawn appropriate in the context of the current research literature? No Competing Interests No competing interests were disclosed. Reviewer Expertise Molecular Pathology, neurogenomics, Parkinson's Disease, Mitochondrial Disease I confirm that I have read this submission and believe that I have an appropriate level of expertise to state that I do not consider it to be of an acceptable scientific standard, for reasons outlined above. reply Respond to this report Responses (1) Author Response 22 Apr 2026 Zheng Liu, Guangxi Key Laboratory of Multimodal Biomarkers and Precision Diagnosis, College of Medical Laboratory and Biotechnology, Guilin Medical University, Guilin, 541004, China Mechanisms Associated with PINK1 Mutations in Parkinson's Disease ABSTRACT Gene names should be in italics PINK1 and PTEN induced kinase 1 are the HGNC approved symbol and name – perhaps include the stable ID; HGNC:14581 Respond: In accordance with the reviewer's suggestion, we have italicized all gene names (e.g., PINK1 ) throughout the manuscript to distinguish them from their protein products. Additionally, we have included the HGNC approved symbol, full name, and the stable ID (HGNC:14581) at the first mention of the gene in the Introduction. “Central to its pathogenesis is the PINK1 gene…” is a broad overgeneralisation that makes it seem like PINK1 is the only cause of PD and not more specific to monogenic early-onset familial PD. Respond: We agree with the reviewer that the original statement was too broad. We have revised the text, “While most cases are sporadic, loss-of-function variants in the PINK1 gene are a primary cause of autosomal recessive early-onset PD.”. We have also clarified that studying PINK1 provides a critical window into mitochondrial dysfunction, which is a shared feature in both familial and sporadic PD. INTRODUCTION Parkinson’s disease is defined as (PD) in the first line, but the abbreviation is not consistently used thereafter Respond: We appreciate the reviewer's attention to detail. We have corrected this throughout the manuscript. Following the initial definition in the first sentence of the Introduction, the abbreviation "PD" is now used consistently in place of the full term. There is a lot of information in the first paragraph that is not appropriately attributed to the original publications. Even a WHO report is mentioned but not referenced. Only the last sentence has an appropriate citation. Respond: We apologize for the insufficient citations in the original draft. We have now added the appropriate references for the epidemiological data and specifically cited the World Health Organization (WHO) report on Parkinson’s disease as requested. “Within four years of diagnosis, there is a rapid and nearly complete loss of dopaminergic markers in the dorsal striatum” neglects the fact that there is a long pro-drome with progressive neurodegeneration. It also reflects the older onset progression of PD and not the early onset monogenic form that is relevant to PINK1. Might need to compare and contrast late vs early onset and idiopathic vs familial. Respond: We appreciate this insightful comment. In the revised Introduction (Paragraph 2), we have addressed this by: 1. Acknowledging the prolonged prodromal phase that precedes motor symptoms. 2. Explicitly distinguishing the clinical phenotype of PINK1 -linked PD from idiopathic cases. We now clarify that PINK1 variants are associated with early-onset Parkinsonism (often before age 45) and a sustained response to levodopa, contrasting this with the older-onset progression of sporadic PD as suggested. Please check whether ‘variant’ is more appropriate than ‘mutation’ Respond: We completely agree with the reviewer. In accordance with current genetic nomenclature guidelines, we have globally replaced the term "mutation" with "variant" throughout the manuscript to describe pathogenic genetic alterations. Not sure how appropriate it is to reference a review for core research results. Reference the original citations where possible. Some citations are quite old. Suggest searching for more contemporary research evidencing the claims made. Respond: We appreciate this valid critique. We have comprehensively audited our reference list. We have removed over-reliance on older review articles and replaced them with highly relevant, contemporary primary research articles. “PINK1 (PTEN-induced putative kinase 1) mutations represent the second most common cause of autosomal recessive early-onset Parkinson’s disease (EOPD), following Parkin mutations” suggests you are talking about the genes, and therefore PINK1 should be in italics and Parkin should be PRKN. Respond: PINK1 has been in italics and Parkin has been changed to PRKN. 2. DIVERSITY OF PINK1 MUTATIONS “Mutations in the PINK1 gene are strongly linked to PD” is suggestive that this is not definitive but rather remains controversial, which certainly isn’t the case. It would seem that this sentence is perfunctory. Respond: the sentence has been rewrote. First paragraph has no references to support the information presented. Respond: the references has been added to the first paragraph. Perhaps the second paragraph could be contextualised with the current extent of PINK1 variants and then perhaps that might help address the next comment. Respond: Thank you for the suggestion. I agree that providing a broader context on the current landscape of PINK1 variants—such as the distinction between pathogenic mutations and benign variants, or the known mutation hotspots—would strengthen the paragraph. This additional detail would not only ground the discussion but also serve as a natural bridge to the subsequent point in the comment." If the variants have been known for over 20 years how do they “…offers valuable guidance for the development of future therapeutic interventions.”? Respond: We have extensively revised this section (now Section 3) to address the reviewer's concerns regarding clarity, referencing, and logical flow: 1. Definitive Language: We have removed the tentative phrasing and now explicitly state that pathogenic variants cause a loss of function, disrupting the neuroprotective response. 2. References Added: We have added the necessary citations to the opening paragraph to support the historical identification and structural clustering of these variants [Valente et al., 2004; Scholten et al., 2020]. 3. Updated Context: We have updated the text to reflect the current landscape, noting that over 70 variants have been cataloged, and we have categorized them by mechanism (kinase inactivation vs. protein instability). 4. Removed Outdated Conclusion: We have removed the generic statement about "future therapeutic guidance." Instead, the section now concludes by summarizing the specific pathological outcome of these variants: the failure to sense mitochondrial depolarization and initiate mitophagy. I would almost introduce normal PINK1 activity and physiology before talking about variants and how the dysfunction of the molecule underpins pathogenesis. As it stands, we’re learning about variants before really understanding the normal function and mechanisms of PINK1 activity. Respond: We are grateful for this excellent suggestion. We agree that a solid understanding of the physiological function of PINK1 is a prerequisite for discussing its pathogenicity. In the revised manuscript, we have inserted a new section entitled "Section 2. Physiological Role and Regulation of PINK1" immediately following the Introduction. In this section, we now detail: 1. The canonical import of PINK1 into healthy mitochondria via the TOM/TIM complexes. 2. Its proteolytic processing by MPP and PARL. 3. Its rapid degradation via the N-end rule pathway. 4. Its function as a molecular sensor for mitochondrial membrane potential. This new section provides the necessary biological context before we introduce the pathogenic variants in the subsequent section (now Section 3).3. PINK1 AND THE PATHOGENESIS OF PD 3.1 PINK1 MUTATIONS AND MITOCHONDRIAL PHOSPHORYLATION The section title suggests PINK1 phosphorylates mitochondria. Instead, a more accurate section title might be PINK1 mutations and target protein phosphorylation Respond: We agree with the reviewer that the original title was imprecise. In the revised manuscript, we have renamed this section (now Section 4.1) to " PINK1 Variants Impair Phosphorylation of Downstream Substrates." This title more accurately reflects the mechanistic reality that PINK1 targets specific proteins—namely Parkin and Ubiquitin—rather than the mitochondrial organelle as a whole. Figure legends should explain a figure as if it were standalone. Figure 1 only has a figure legend title and no supporting description of what is depicted. From author instructions for Reviews: “Titles and legends: Each figure or table should have a concise title of no more than 15 words. A legend for each figure and table should also be provided that briefly describes the key points and explains any symbols and abbreviations used. The legend should be sufficiently detailed so that the figure or table can stand alone from the main text.” This is currently not the case for Figure 1. Respond: We apologize for this omission. We have provided a comprehensive, standalone legend for Figure 1 that thoroughly explains the depicted mechanisms, including basal turnover, mitophagy initiation (highlighting OPTN/NDP52), and the disease state. All abbreviations used in the figure are now explicitly defined in the legend. Additionally, we have ensured that Figure 1 is properly cited and integrated within the relevant mechanistic sections of the main text to guide the reader effectively. 3.2 PINK1 MUTATIONS AND ABNORMAL MITOPHAGY PATHWAYS Parkin is introduced here as if it is the first time it is introduced with its function etc. yet it appears in all sections above While p62 was originally the best characterised autophagy receptor for Parkin-mediated mitophagy, there are several others that have been identified as being more prominent, including optineurin and NDP52. While NBR1 and TAX1BP1 are less prominent like p62. Respond: We are grateful to the reviewer for their careful reading and for pointing out this critical evolution in the field. We have made two major revisions to this section (now Section 4.2) to fully address these concerns: 1. Removal of redundant Parkin introduction: We apologize for the redundancy. With the addition of the new "Section 2. Physiological Role and Regulation of PINK1" earlier in the manuscript, Parkin's baseline function is now appropriately introduced upon its first mention. We have carefully revised Section 4.2 to remove the repetitive introduction of Parkin, ensuring a smoother logical flow. 2. Updating the mitophagy receptor consensus: We have significantly revised the text to reflect the current consensus on autophagy receptors. As the reviewer correctly pointed out, we now explicitly state that Optineurin (OPTN) and NDP52 are the primary receptors essential for mitophagy. We also briefly acknowledge that p62, NBR1, and TAX1BP1 play less prominent roles. Furthermore, we now detail how PINK1-mediated phosphorylation of ubiquitin serves as the specific signal to recruit OPTN and NDP52. Key citations have been added to support this updated, contemporary perspective.OVERALL Overall I found this short review to provide limited insight into the role of PINK1 in Parkinson’s disease with often outdated or incomplete supporting literature. PINK1 and Parkin have considerable influence outside of mitophagy, for instance PINK1 and Parkin were shown to be central to innate immunity in a knockout model where PD was induced by intestinal infection. Additionally, mitochondrial dysfunction can be the cause or corollary in PD and while this review takes the simplistic and repeated view of PINK1 and Parkin centrality to mitophagy, it is a limited view and negates the peripheral complexities and multifaceted nature of PD pathogenesis. As such, this review does nothing more than to reiterate information that have been presented ad nauseum without opinion or insight into the potential for therapeutic treatment that has thus far failed and remains an endeavour for the entire field. While the review is generally well written it lacks originality in insight and opinion that would drive the field in a particular direction, as a good review should do. As a result, I think this review is severely lacking and adds little to the literature that hasn’t already been presented numerous times previously. Respond: We are deeply grateful for this profound and constructive critique, which has fundamentally elevated the quality of our manuscript. We fully agree that our previous draft was too narrowly focused on canonical mitophagy and lacked forward-looking translational insights. To address this, we have made substantial additions: 1. Expansion Beyond Mitophagy (Innate Immunity & Gut-Brain Axis): We have added a completely new section (Section 4.3: Beyond Mitophagy: PINK1 and Neuroinflammation). As astutely suggested by the reviewer, we now extensively discuss the role of PINK1 as a critical immunological checkpoint. We specifically highlight the seminal Nature study demonstrating that intestinal infection triggers autoimmune mechanisms in Pink1 -knockout mice via mitochondrial antigen presentation (Matheoud et al., 2019) , as well as the activation of the cGAS-STING pathway. 2. Translational Relevance and Therapeutic Insight: We have added another new section (Section 4.4: Therapeutic Implications) to provide the missing "insight and opinion" on drug development. We critically evaluate novel precision medicine strategies, specifically highlighting the amplification of kinase activity (via Kinetin) and the promising strategy of bypassing mitophagy blockades using USP30 inhibitors. 3. We believe these major revisions transform the manuscript from a mere descriptive summary into a critical, forward-looking review that offers a new framework for understanding PINK1 pathogenesis and developing targeted therapies. View more View less Competing Interests No competing interests were disclosed. reply Respond Report a concern Davis RL. Peer Review Report For: Mechanisms Associated with PINK1 Mutations in Parkinson's Disease [version 1; peer review: 1 approved, 1 not approved] . F1000Research 2025, 14 :1138 ( https://doi.org/10.5256/f1000research.187509.r425648) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. The direct URL for this report is: https://f1000research.com/articles/14-1138/v1#referee-response-425648 keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2026 Mohamed E. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 29 Dec 2025 | for Version 1 Eman Ezzeldien Mohamed , Beni-Suef University, Beni-Suef, Egypt 0 Views copyright © 2026 Mohamed E. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. format_quote Cite this report speaker_notes Responses (1) Approved info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions Reviewer: This manuscript addresses an important topic by reviewing the mechanisms linking PINK1 mutations to Parkinson’s disease. The review is generally well-referenced and provides informative coverage of mitochondrial dysfunction, autophagy, and oxidative stress. 1. The Introduction should more clearly define the scope of the review and highlight existing knowledge gaps. Several sections remain largely descriptive, and greater critical analysis of the literature is needed. 2. the Review should better explain the mechanistic reasons behind the reported pathological outcomes. 3. the clinical and translational relevance of PINK1 mutations could be more explicitly addressed. Improving integration between the figure and the main text would also enhance clarity. Is the topic of the review discussed comprehensively in the context of the current literature? Yes Are all factual statements correct and adequately supported by citations? Partly Is the review written in accessible language? Yes Are the conclusions drawn appropriate in the context of the current research literature? Yes Competing Interests No competing interests were disclosed. Reviewer Expertise physiology I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. reply Respond to this report Responses (1) Author Response 22 Apr 2026 Zheng Liu, Guangxi Key Laboratory of Multimodal Biomarkers and Precision Diagnosis, College of Medical Laboratory and Biotechnology, Guilin Medical University, Guilin, 541004, China This manuscript addresses an important topic by reviewing the mechanisms linking PINK1 mutations to Parkinson’s disease. The review is generally well-referenced and provides informative coverage of mitochondrial dysfunction, autophagy, and oxidative stress. 1. The Introduction should more clearly define the scope of the review and highlight existing knowledge gaps. Several sections remain largely descriptive, and greater critical analysis of the literature is needed. Respond: We agree. We revised the Introduction's final paragraph to clearly define the review's scope and highlight knowledge gaps, specifically PINK1's non-mitophagic roles in innate immunity. We also cited seminal studies on the gut-brain axis and inflammation, such as Matheoud et al. (2019), to enhance our critical analysis. 2. the Review should better explain the mechanistic reasons behind the reported pathological outcomes. Respond: Thank you for the suggestion. We significantly deepened the mechanistic discussions. In Section 3, we detail how specific variants fail to phosphorylate Ubiquitin/Parkin at Ser65. In Section 4.2, we explain how this failure blocks the recruitment of key autophagy receptors (OPTN and NDP52), leading to the accumulation of ROS-producing mitochondria that mechanically drives neurodegeneration. 3. the clinical and translational relevance of PINK1 mutations could be more explicitly addressed. Improving integration between the figure and the main text would also enhance clarity. Respond: We appreciate these suggestions and made two major updates: 1.Translational Relevance: We added a new section (Section 4.4: Therapeutic Implications) exploring precision medicine strategies, highlighting neo-substrates (e.g., Kinetin) and USP30 inhibitors. 2. Figure Integration: We rewrote the legend for Figure 1 so it fully explains the mechanisms and stands alone. We also improved its integration by citing it at key mechanistic junctures (e.g., Sections 2 and 4.2) in the main text. View more View less Competing Interests None. reply Respond Report a concern Mohamed EE. Peer Review Report For: Mechanisms Associated with PINK1 Mutations in Parkinson's Disease [version 1; peer review: 1 approved, 1 not approved] . F1000Research 2025, 14 :1138 ( https://doi.org/10.5256/f1000research.187509.r440954) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. The direct URL for this report is: https://f1000research.com/articles/14-1138/v1#referee-response-440954 Alongside their report, reviewers assign a status to the article: Approved - the paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations - A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved - fundamental flaws in the paper seriously undermine the findings and conclusions Adjust parameters to alter display View on desktop for interactive features Includes Interactive Elements View on desktop for interactive features Competing Interests Policy Provide sufficient details of any financial or non-financial competing interests to enable users to assess whether your comments might lead a reasonable person to question your impartiality. Consider the following examples, but note that this is not an exhaustive list: Examples of 'Non-Financial Competing Interests' Within the past 4 years, you have held joint grants, published or collaborated with any of the authors of the selected paper. You have a close personal relationship (e.g. parent, spouse, sibling, or domestic partner) with any of the authors. You are a close professional associate of any of the authors (e.g. scientific mentor, recent student). You work at the same institute as any of the authors. You hope/expect to benefit (e.g. favour or employment) as a result of your submission. You are an Editor for the journal in which the article is published. Examples of 'Financial Competing Interests' You expect to receive, or in the past 4 years have received, any of the following from any commercial organisation that may gain financially from your submission: a salary, fees, funding, reimbursements. You expect to receive, or in the past 4 years have received, shared grant support or other funding with any of the authors. You hold, or are currently applying for, any patents or significant stocks/shares relating to the subject matter of the paper you are commenting on. Stay Updated Sign up for content alerts and receive a weekly or monthly email with all newly published articles Register with F1000Research Already registered? Sign in Not now, thanks close PLEASE NOTE If you are an AUTHOR of this article, please check that you signed in with the account associated with this article otherwise we cannot automatically identify your role as an author and your comment will be labelled as a “User Comment”. If you are a REVIEWER of this article, please check that you have signed in with the account associated with this article and then go to your account to submit your report, please do not post your review here. If you do not have access to your original account, please contact us . All commenters must hold a formal affiliation as per our Policies . The information that you give us will be displayed next to your comment. User comments must be in English, comprehensible and relevant to the article under discussion. We reserve the right to remove any comments that we consider to be inappropriate, offensive or otherwise in breach of the User Comment Terms and Conditions . Commenters must not use a comment for personal attacks. When criticisms of the article are based on unpublished data, the data should be made available. I accept the User Comment Terms and Conditions Please confirm that you accept the User Comment Terms and Conditions. Affiliation ✕ refresh Please enter your institution. Note: To add your institution or organisation, start typing the name and then select the correct name from the list. Where applicable, the name will appear in both the original language and in English. Do not paste in the name. If the name does not appear in the drop-down list, we will display the information you have entered. ✕ refresh Country/Region * USA UK Canada China France Germany Afghanistan Aland Islands Albania Algeria American Samoa Andorra Angola Anguilla Antarctica Antigua and Barbuda Argentina Armenia Aruba Australia Austria Azerbaijan Bahamas Bahrain Bangladesh Barbados Belarus Belgium Belize Benin Bermuda Bhutan Bolivia Bosnia and Herzegovina Botswana Bouvet Island Brazil British Indian Ocean Territory British Virgin Islands Brunei Bulgaria Burkina Faso Burundi Cambodia Cameroon Canada Cape Verde Cayman Islands Central African Republic Chad Chile China Christmas Island Cocos (Keeling) Islands Colombia Comoros Congo Cook Islands Costa Rica Cote d'Ivoire Croatia Cuba Cyprus Czech Republic Democratic Republic of the Congo Denmark Djibouti Dominica Dominican Republic Ecuador Egypt El Salvador Equatorial Guinea Eritrea Estonia Ethiopia Falkland Islands Faroe Islands Federated States of Micronesia Fiji Finland France French Guiana French Polynesia French Southern Territories Gabon Georgia Germany Ghana Gibraltar Greece Greenland Grenada Guadeloupe Guam Guatemala Guernsey Guinea Guinea-Bissau Guyana Haiti Heard Island and Mcdonald Islands Holy See (Vatican City State) Honduras Hong Kong Hungary Iceland India Indonesia Iran Iraq Ireland Israel Italy Jamaica Japan Jersey Jordan Kazakhstan Kenya Kiribati Kosovo (Serbia and Montenegro) Kuwait Kyrgyzstan Lao People's Democratic Republic Latvia Lebanon Lesotho Liberia Libya Liechtenstein Lithuania Luxembourg Macao Madagascar Malawi Malaysia Maldives Mali Malta Marshall Islands Martinique Mauritania Mauritius Mayotte Mexico Minor Outlying Islands of the United States Moldova Monaco Mongolia Montenegro Montserrat Morocco Mozambique Myanmar Namibia Nauru Nepal Netherlands Antilles New Caledonia New Zealand Nicaragua Niger Nigeria Niue Norfolk Island North Korea North Macedonia Northern Mariana Islands Norway Oman Pakistan Palau Palestinian Territory Panama Papua New Guinea Paraguay Peru Philippines Pitcairn Poland Portugal Puerto Rico Qatar Reunion Romania Russian Federation Rwanda Saint Helena Saint Kitts and Nevis Saint Lucia Saint Pierre and Miquelon Saint Vincent and the Grenadines Samoa San Marino Sao Tome and Principe Saudi Arabia Senegal Serbia Seychelles Sierra Leone Singapore Slovakia Slovenia Solomon Islands Somalia South Africa South Georgia and the South Sandwich Is South Korea South Sudan Spain Sri Lanka Sudan Suriname Svalbard and Jan Mayen Swaziland Sweden Switzerland Syria Taiwan Tajikistan Tanzania Thailand The Gambia The Netherlands Timor-Leste Togo Tokelau Tonga Trinidad and Tobago Tunisia Turkey Turkmenistan Turks and Caicos Islands Tuvalu UK USA Uganda Ukraine United Arab Emirates United States Virgin Islands Uruguay Uzbekistan Vanuatu Venezuela Vietnam Wallis and Futuna West Bank and Gaza Strip Western Sahara Yemen Zambia Zimbabwe Please select your country/region. You must enter a comment. Competing Interests Please disclose any competing interests that might be construed to influence your judgment of the article's or peer review report's validity or importance. Competing Interests Policy Provide sufficient details of any financial or non-financial competing interests to enable users to assess whether your comments might lead a reasonable person to question your impartiality. Consider the following examples, but note that this is not an exhaustive list: Examples of 'Non-Financial Competing Interests' Within the past 4 years, you have held joint grants, published or collaborated with any of the authors of the selected paper. You have a close personal relationship (e.g. parent, spouse, sibling, or domestic partner) with any of the authors. You are a close professional associate of any of the authors (e.g. scientific mentor, recent student). You work at the same institute as any of the authors. You hope/expect to benefit (e.g. favour or employment) as a result of your submission. You are an Editor for the journal in which the article is published. Examples of 'Financial Competing Interests' You expect to receive, or in the past 4 years have received, any of the following from any commercial organisation that may gain financially from your submission: a salary, fees, funding, reimbursements. You expect to receive, or in the past 4 years have received, shared grant support or other funding with any of the authors. You hold, or are currently applying for, any patents or significant stocks/shares relating to the subject matter of the paper you are commenting on. Please state your competing interests The comment has been saved. An error has occurred. Please try again. Cancel Post var lTitle = "Mechanisms Associated with PINK1 Mutations...".replace("'", ''); var linkedInUrl = "http://www.linkedin.com/shareArticle?url=https://f1000research.com/articles/14-1138/v1" + "&title=" + encodeURIComponent(lTitle) + "&summary=" + encodeURIComponent('Read the article by '); var deliciousUrl = "https://del.icio.us/post?url=https://f1000research.com/articles/14-1138/v1&title=" + encodeURIComponent(lTitle); var redditUrl = "http://reddit.com/submit?url=https://f1000research.com/articles/14-1138/v1" + "&title=" + encodeURIComponent(lTitle); linkedInUrl += encodeURIComponent('Dan H et al.'); var offsetTop = /chrome/i.test( navigator.userAgent ) ? 4 : -10; var addthis_config = { ui_offset_top: offsetTop, services_compact : "facebook,twitter,www.linkedin.com,www.mendeley.com,reddit.com", services_expanded : "facebook,twitter,www.linkedin.com,www.mendeley.com,reddit.com", services_custom : [ { name: "LinkedIn", url: linkedInUrl, icon:"/img/icon/at_linkedin.svg" }, { name: "Mendeley", url: "http://www.mendeley.com/import/?url=https://f1000research.com/articles/14-1138/v1/mendeley", icon:"/img/icon/at_mendeley.svg" }, { name: "Reddit", url: redditUrl, icon:"/img/icon/at_reddit.svg" }, ] }; var addthis_share = { url: "https://f1000research.com/articles/14-1138", templates : { twitter : "Mechanisms Associated with PINK1 Mutations in Parkinson\'s Disease. Dan H et al., published by " + "@F1000Research" + ", https://f1000research.com/articles/14-1138/v1" } }; if (typeof(addthis) != "undefined"){ addthis.addEventListener('addthis.ready', checkCount); addthis.addEventListener('addthis.menu.share', checkCount); } $(".f1r-shares-twitter").attr("href", "https://twitter.com/intent/tweet?text=" + addthis_share.templates.twitter); $(".f1r-shares-facebook").attr("href", "https://www.facebook.com/sharer/sharer.php?u=" + addthis_share.url); $(".f1r-shares-linkedin").attr("href", addthis_config.services_custom[0].url); $(".f1r-shares-reddit").attr("href", addthis_config.services_custom[2].url); $(".f1r-shares-mendelay").attr("href", addthis_config.services_custom[1].url); function checkCount(){ setTimeout(function(){ $(".addthis_button_expanded").each(function(){ var count = $(this).text(); if (count !== "" && count != "0") $(this).removeClass("is-hidden"); else $(this).addClass("is-hidden"); }); }, 1000); } close How to cite this report {{reportCitation}} Cancel Copy Citation Details $(function(){R.ui.buttonDropdowns('.dropdown-for-downloads');}); $(function(){R.ui.toolbarDropdowns('.toolbar-dropdown-for-downloads');}); $.get("/articles/acj/170090/187509") new F1000.Clipboard(); new F1000.ThesaurusTermsDisplay("articles", "article", "187509"); $(document).ready(function() { $( "#frame1" ).on('load', function() { var mydiv = $(this).contents().find("div"); var h = mydiv.height(); console.log(h) }); var tooltipLivingFigure = jQuery(".interactive-living-figure-label .icon-more-info"), titleLivingFigure = tooltipLivingFigure.attr("title"); tooltipLivingFigure.simpletip({ fixed: true, position: ["-115", "30"], baseClass: 'small-tooltip', content:titleLivingFigure + " " }); tooltipLivingFigure.removeAttr("title"); $("body").on("click", ".cite-living-figure", function(e) { e.preventDefault(); var ref = $(this).attr("data-ref"); $(this).closest(".living-figure-list-container").find("#" + ref).fadeIn(200); }); $("body").on("click", ".close-cite-living-figure", function(e) { e.preventDefault(); $(this).closest(".popup-window-wrapper").fadeOut(200); }); $(document).on("mouseup", function(e) { var metricsContainer = $(".article-metrics-popover-wrapper"); if (!metricsContainer.is(e.target) && metricsContainer.has(e.target).length === 0) { $(".article-metrics-close-button").click(); } }); var articleId = $('#articleId').val(); if($("#main-article-count-box").attachArticleMetrics) { $("#main-article-count-box").attachArticleMetrics(articleId, { articleMetricsView: true }); } }); var figshareWidget = $(".new_figshare_widget"); if (figshareWidget.length > 0) { window.figshare.load("f1000", function(Widget) { // Select a tag/tags defined in your page. In this tag we will place the widget. _.map(figshareWidget, function(el){ var widget = new Widget({ articleId: $(el).attr("figshare_articleId") //height:300 // this is the height of the viewer part. [Default: 550] }); widget.initialize(); // initialize the widget widget.mount(el); // mount it in a tag that's on your page // this will save the widget on the global scope for later use from // your JS scripts. This line is optional. //window.widget = widget; }); }); } close Error Close Add Reset F1000.MICROSERVICES.AFFILIATION = ''; $(document).ready(function () { $('.js-affiliations-form').each((index, form) => { new AffiliationForm({ formId: form.id, institutionErrorSelector: '.comment-enter-institution', departmentErrorSelector: '.comment-enter-department', placeSelector: '.js-add-comment-place', stateSelector: '.js-add-comment-state', zipCodeSelector: '.js-add-comment-zipcode', countrySelector: '.js-add-comment-country', countryErrorSelector: '.comment-enter-country', }); }); }); $(document).ready(function () { var reportIds = { "427910": 0, "427911": 0, "427908": 0, "427909": 0, "427906": 0, "427907": 0, "427914": 0, "427915": 0, "427912": 0, "427913": 0, "477607": 0, "425646": 0, "425647": 0, "425644": 0, "425645": 0, "477608": 0, "425652": 0, "425653": 0, "425650": 0, "425651": 0, "425648": 20, "425649": 0, "480071": 0, "480079": 0, "480078": 0, "480077": 0, "480076": 0, "480075": 0, "480074": 0, "480073": 0, "480072": 0, "480080": 0, "481887": 0, "481886": 0, "481885": 0, "481894": 0, "481893": 0, "481892": 0, "481891": 0, "481890": 0, "481889": 0, "481888": 0, "484591": 0, "439022": 0, "484590": 0, "439023": 0, "439020": 0, "439021": 0, "484599": 0, "436982": 0, "440950": 0, "484598": 0, "436983": 0, "440951": 0, "484597": 0, "436980": 0, "439028": 0, "484596": 0, "436981": 0, "439029": 0, "440949": 0, "484595": 0, "436978": 0, "439026": 0, "484594": 0, "436979": 0, "439027": 0, "484593": 0, "436976": 0, "439024": 0, "484592": 0, "436977": 0, "439025": 0, "440958": 0, "440956": 0, "440957": 0, "440954": 14, "440955": 0, "436984": 0, "440952": 0, "436985": 0, "440953": 0, }; $(".referee-response-container,.js-referee-report").each(function(index, el) { var reportId = $(el).attr("data-reportid"), reportCount = reportIds[reportId] || 0; $(el).find(".comments-count-container,.js-referee-report-views").html(reportCount); }); var uuidInput = $("#article_uuid"), oldUUId = uuidInput.val(), newUUId = "c21d77ee-eb80-4461-8217-bc59c731ba6c"; uuidInput.val(newUUId); $("a[href*='article_uuid=']").each(function(index, el) { var newHref = $(el).attr("href").replace(oldUUId, newUUId); $(el).attr("href", newHref); }); }); An innovative open access publishing platform offering rapid publication and open peer review, whilst supporting data deposition and sharing. Browse Gateways Collections How it Works Contact For Developers Cookie Notice Privacy Notice RSS Submit Your Research Follow us © 2012-2026 F1000 Research Ltd. ISSN 2046-1402 | Legal | Partner of Research4Life • CrossRef • ORCID • FAIRSharing R.templateTests.simpleTemplate = R.template(' $text $text $text $text $text '); R.templateTests.runTests(); var F1000platform = new F1000.Platform({ name: "f1000research", displayName: "F1000Research", hostName: "f1000research.com", id: "1", editorialEmail: "[email protected]", infoEmail: "[email protected]", usePmcStats: true }); $(function(){R.ui.dropdowns('.dropdown-for-authors, .dropdown-for-about, .dropdown-for-myresearch');}); // $(function(){R.ui.dropdowns('.dropdown-for-referees');}); $(document).ready(function () { if ($(".cookie-warning").is(":visible")) { $(".sticky").css("margin-bottom", "35px"); $(".devices").addClass("devices-and-cookie-warning"); } $(".cookie-warning .close-button").click(function (e) { $(".devices").removeClass("devices-and-cookie-warning"); $(".sticky").css("margin-bottom", "0"); }); $("#tweeter-feed .tweet-message").each(function (i, message) { var self = $(message); self.html(linkify(self.html())); }); $(".partner").on("mouseenter mouseleave", function() { $(this).find(".gray-scale, .colour").toggleClass("is-hidden"); }); }); Sign In Remember me Forgotten your password? Sign In Cancel Email or password not correct. Please try again Please wait... $(function(){ // Note: All the setup needs to run against a name attribute and *not* the id due the clonish // nature of facebox... $("a[id=googleSignInButton]").click(function(event){ event.preventDefault(); $("input[id=oAuthSystem]").val("GOOGLE"); $("form[id=oAuthForm]").submit(); }); $("a[id=facebookSignInButton]").click(function(event){ event.preventDefault(); $("input[id=oAuthSystem]").val("FACEBOOK"); $("form[id=oAuthForm]").submit(); }); $("a[id=orcidSignInButton]").click(function(event){ event.preventDefault(); $("input[id=oAuthSystem]").val("ORCID"); $("form[id=oAuthForm]").submit(); }); }); If you've forgotten your password, please enter your email address below and we'll send you instructions on how to reset your password. The email address should be the one you originally registered with F1000. Email address not valid, please try again You registered with F1000 via Google, so we cannot reset your password. To sign in, please click here . If you still need help with your Google account password, please click here . You registered with F1000 via Facebook, so we cannot reset your password. To sign in, please click here . If you still need help with your Facebook account password, please click here . Code not correct, please try again Reset password Cancel Email us for further assistance. Server error, please try again. If your email address is registered with us, we will email you instructions to reset your password. If you think you should have received this email but it has not arrived, please check your spam filters and/or contact for further assistance. Please wait... Register $(document).ready(function () { signIn.createSignInAsRow($("#sign-in-form-gfb-popup")); $(".target-field").each(function () { var uris = $(this).val().split("/"); if (uris.pop() === "login") { $(this).val(uris.toString().replace(",","/")); } }); });