A novel function of glyoxalase domain containing protein 4 (GLOD4) is associated with neuron dysfunction and neurodegeneration

A novel function of glyoxalase domain containing protein 4 (GLOD4) is associated with neuron dysfunction and neurodegeneration | 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 A novel function of glyoxalase domain containing protein 4 (GLOD4) is associated with neuron dysfunction and neurodegeneration Irene Griswold-Prenner, Sarah Wright, Vu Dang, Sami Hussain, Prasanna Kandel, and 16 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6100422/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted You are reading this latest preprint version Abstract Tyrosine nitration alters the structure, function, and/or cellular localization of proteins1,2 and is implicated in the pathology of multiple diseases1-3. Although protein nitration is assumed to proceed via nonspecific chemical mechanisms, it is highly selective, suggesting the possibility of enzymatic catalysis. Here, we showed that glyoxalase domain-containing protein 4 (GLOD4), a previously uncharacterized protein, is an enzyme that catalyzes selective protein nitration. A primary in vivo target for GLOD4-mediated nitration is alpha-synuclein (α-syn), which is central to the development of Parkinson’s disease (PD) and related disorders. GLOD-dependent tyrosine nitration of alpha synuclein was demonstrated in both neuronal cells and in a murine model of neuronal toxicity. Furthermore, GLOD4 impaired neuronal connectivity and propagated preformed fibril (PFF)-induced α-syn aggregation in iPSC-derived dopaminergic neurons. In the A53T α-synuclein transgenic mouse models, GLOD4 knockout (KO) reduced paralysis and the PFF-induced spread of pathological α-syn. Overall, our results identify a novel function of GLOD4 as a mediator of α-syn nitration with implications in α-syn pathology and neurodegeneration. Therefore, understanding the role of GLOD4 and other nitrating enzymes in biology and diseases such as PD, cancer, and autoimmunity may unearth novel pathophysiological mechanisms and potential interventions. Biological sciences/Neuroscience/Diseases of the nervous system/Parkinson's disease Biological sciences/Biochemistry/Enzymes Tyrosine nitration 3-nitrotyrosine nitrases autonitration posttranslational modifications glyoxalase domain containing protein 4 (GLOD4) vicinal oxygen chelate superfamily Parkinson’s disease alpha-synuclein Full Text Additional Declarations Yes there is potential Competing Interest. Several authors are option and/or share holders in Nitrase Therapeutics Cite Share Download PDF Status: Under Review 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-6100422","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":427403392,"identity":"d38d935b-34c2-4b70-9bd6-ebce927d27bf","order_by":0,"name":"Irene 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neurodegeneration","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":false,"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":"nature-portfolio","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"","title":"Nature Portfolio","twitterHandle":"","acdcEnabled":false,"dfaEnabled":false,"editorialSystem":"ejp","reportingPortfolio":"","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Tyrosine nitration, 3-nitrotyrosine, nitrases, autonitration, posttranslational modifications, glyoxalase domain containing protein 4 (GLOD4), vicinal oxygen chelate superfamily, Parkinson’s disease, alpha-synuclein","lastPublishedDoi":"10.21203/rs.3.rs-6100422/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6100422/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"Tyrosine nitration alters the structure, function, and/or cellular localization of proteins1,2 and is implicated in the pathology of multiple diseases1-3. Although protein nitration is assumed to proceed via nonspecific chemical mechanisms, it is highly selective, suggesting the possibility of enzymatic catalysis. Here, we showed that glyoxalase domain-containing protein 4 (GLOD4), a previously uncharacterized protein, is an enzyme that catalyzes selective protein nitration. A primary in vivo target for GLOD4-mediated nitration is alpha-synuclein (α-syn), which is central to the development of Parkinson’s disease (PD) and related disorders. GLOD-dependent tyrosine nitration of alpha synuclein was demonstrated in both neuronal cells and in a murine model of neuronal toxicity. Furthermore, GLOD4 impaired neuronal connectivity and propagated preformed fibril (PFF)-induced α-syn aggregation in iPSC-derived dopaminergic neurons. In the A53T α-synuclein transgenic mouse models, GLOD4 knockout (KO) reduced paralysis and the PFF-induced spread of pathological α-syn. Overall, our results identify a novel function of GLOD4 as a mediator of α-syn nitration with implications in α-syn pathology and neurodegeneration. Therefore, understanding the role of GLOD4 and other nitrating enzymes in biology and diseases such as PD, cancer, and autoimmunity may unearth novel pathophysiological mechanisms and potential interventions.","manuscriptTitle":"A novel function of glyoxalase domain containing protein 4 (GLOD4) is associated with neuron dysfunction and neurodegeneration","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-03-12 14:51:59","doi":"10.21203/rs.3.rs-6100422/v1","editorialEvents":[],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"nature-neuroscience","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"neuro","sideBox":"Learn more about [Nature Neuroscience](http://www.nature.com/neuro/)","snPcode":"","submissionUrl":"","title":"Nature Neuroscience","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature Research","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"e326b568-311d-423d-aadf-da6d36283ca5","owner":[],"postedDate":"March 12th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":45542408,"name":"Biological sciences/Neuroscience/Diseases of the nervous system/Parkinson's disease"},{"id":45542409,"name":"Biological sciences/Biochemistry/Enzymes"}],"tags":[],"updatedAt":"2025-04-14T11:42:04+00:00","versionOfRecord":[],"versionCreatedAt":"2025-03-12 14:51:59","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6100422","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6100422","identity":"rs-6100422","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}