Extracellular vesicle α-synuclein seeds drive divergent phenoconversion from iRBD to Parkinsonism

Extracellular vesicle α-synuclein seeds drive divergent phenoconversion from iRBD to Parkinsonism | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (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;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Extracellular vesicle α-synuclein seeds drive divergent phenoconversion from iRBD to Parkinsonism Jun Liu, Fangzheng Chen, Yan Shen, Hui Dong, Shenqing Zhang, Haonan Xiao, and 10 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8466772/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Idiopathic rapid eye movement (REM) sleep behaviour disorder (iRBD) is a prodromal ɑ-synucleinopathy that often precedes Parkinson’s disease (PD) or multiple system atrophy (MSA), but the determinants of divergent conversion are unknown. We isolated neuronal extracellular vesicles (NEV) from PD plasma and oligodendroglial extracellular vesicles (OEV) from MSA plasma and found that they harbour disease-specific ɑ-synuclein seeds with mutually exclusive seeding activity. These seeds amplify into distinct fibril strains, with MSA-OEV-amplified fibrils displaying greater cytotoxicity. To model conversion, we primed the sublaterodorsal tegmental nucleus, a key REM-atonia hub, with neuronal or oligodendroglial ɑ-synuclein expression and delivered matched patient EV. Either cellular priming alone produced only mild REM sleep without atonia, whereas EV seeding triggered robust iRBD-like phenotypes and progressive neurodegeneration. PD-NEV drove early nigrostriatal pathology with prominent hyposmia, while MSA-OEV preferentially produced severe autonomic dysfunction. Together, our data identify a seed-milieu matching principle that links a shared prodrome to distinct ɑ-synucleinopathies, provide complementary iRBD-to-parkinsonism mouse models, and support blood EV seeding signatures as minimally invasive biomarkers to forecast conversion and guide early intervention. Health sciences/Neurology/Neurological disorders/Neurodegeneration Biological sciences/Neuroscience/Diseases of the nervous system/Parkinson's disease rapid eye movement sleep behavior disorder Parkinson’s disease multiple system atrophy ɑ-synuclein extracellular vesicles Full Text Additional Declarations There is NO Competing Interest. Supplementary Files SupplementaryTable1.xlsx Supplementary information: Supplementary Table 1 C.L.J.L.nrreportingsummary.pdf Reporting summary C.L.J.L.nreditorialpolicychecklist.pdf NR-editorial-policy-checklist sourcedata.zip Dataset 1 C.L.J.L.ARRIVEAuthorChecklist.pdf ARRIVE Author Checklist SupplementaryInformation.pdf Supplementary information Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8466772","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":571621632,"identity":"5243b67e-09db-4e03-88c9-ffb74d45efef","order_by":0,"name":"Jun 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Parkinsonism","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":true,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"rapid eye movement sleep behavior disorder, Parkinson’s disease, multiple system atrophy, ɑ-synuclein, extracellular vesicles","lastPublishedDoi":"10.21203/rs.3.rs-8466772/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8466772/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eIdiopathic rapid eye movement (REM) sleep behaviour disorder (iRBD) is a prodromal ɑ-synucleinopathy that often precedes Parkinson\u0026rsquo;s disease (PD) or multiple system atrophy (MSA), but the determinants of divergent conversion are unknown. We isolated neuronal extracellular vesicles (NEV) from PD plasma and oligodendroglial extracellular vesicles (OEV) from MSA plasma and found that they harbour disease-specific ɑ-synuclein seeds with mutually exclusive seeding activity. These seeds amplify into distinct fibril strains, with MSA-OEV-amplified fibrils displaying greater cytotoxicity. To model conversion, we primed the sublaterodorsal tegmental nucleus, a key REM-atonia hub, with neuronal or oligodendroglial ɑ-synuclein expression and delivered matched patient EV. Either cellular priming alone produced only mild REM sleep without atonia, whereas EV seeding triggered robust iRBD-like phenotypes and progressive neurodegeneration. PD-NEV drove early nigrostriatal pathology with prominent hyposmia, while MSA-OEV preferentially produced severe autonomic dysfunction. Together, our data identify a seed-milieu matching principle that links a shared prodrome to distinct ɑ-synucleinopathies, provide complementary iRBD-to-parkinsonism mouse models, and support blood EV seeding signatures as minimally invasive biomarkers to forecast conversion and guide early intervention.\u003c/p\u003e","manuscriptTitle":"Extracellular vesicle α-synuclein seeds drive divergent phenoconversion from iRBD to Parkinsonism","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-01-09 15:11:15","doi":"10.21203/rs.3.rs-8466772/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"d70000c6-677f-4242-ab8f-2955ee69603a","owner":[],"postedDate":"January 9th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":60831236,"name":"Health sciences/Neurology/Neurological disorders/Neurodegeneration"},{"id":60831237,"name":"Biological sciences/Neuroscience/Diseases of the nervous system/Parkinson's disease"}],"tags":[],"updatedAt":"2026-02-10T16:34:23+00:00","versionOfRecord":[],"versionCreatedAt":"2026-01-09 15:11:15","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8466772","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8466772","identity":"rs-8466772","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}