Secondary nucleation of α-Synuclein drives Mitochondria dysfunctions and Lewy body formation in Parkinson’s Disease

Secondary nucleation of α-Synuclein drives Mitochondria dysfunctions and Lewy body formation in Parkinson’s Disease | 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 Secondary nucleation of α-Synuclein drives Mitochondria dysfunctions and Lewy body formation in Parkinson’s Disease Suman De, Emily Prescott, Jiapeng Wei, Emma Garland, Agnieszka Urbanek, and 16 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7657706/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 The seeding of α-Synuclein (αSyn) is a key driver of Lewy pathology propagation in Parkinson’s disease (PD) and forms the basis for recent diagnostic success. However, it remains unclear how the structural and biochemical features of αSyn seeds dictate their propagation efficiency, capacity to induce Lewy body formation, and resulting cellular toxicity. Using genetic and idiopathic PD cell models, we map the pathogenic cascade beginning with the seed-driven conversion of endogenous αSyn, followed by impaired degradation, mitochondrial dysfunction, and ultimately Lewy body formation. By integrating functional readouts kinetic modelling, we identify secondary nucleation as the predominant mechanism generating toxic αSyn aggregation intermediates, identifying the critical process that links seeding to pathology. Extending this framework to PD brain, we quantitatively correlate seeding capacity with the spatiotemporal spread and severity of Lewy pathology, revealing a mechanistic connection between αSyn aggregation dynamics and disease progression at molecular, cellular, and anatomical levels. Health sciences/Diseases/Neurological disorders/Parkinson's disease Biological sciences/Biophysics/Single-molecule biophysics Biological sciences/Molecular biology/Protein folding/Protein aggregation Biological sciences/Neuroscience/Molecular neuroscience Full Text Additional Declarations Yes there is potential Competing Interest. H.M. is CEO and co-founder of Mitotype Precision Labs. All other authors have no conflict of interest Supplementary Files SupplementaryTableMassspecPrescottetal.xlsx Supplementary Table_Mass spec SupportinginfoPrescottetal.docx Supporting info_Prescott et al.docx 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. 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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-7657706","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":517813179,"identity":"5608632d-d3c8-47cf-929c-8f4470ddc63c","order_by":0,"name":"Suman 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