α-Synuclein driven cell susceptibility in Parkinson’s disease

α-Synuclein driven cell susceptibility 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 α-Synuclein driven cell susceptibility in Parkinson’s disease Steven Lee, Jonathan Breiter, Joseph Beckwith, Emma Brock, Joanne Lachica, and 7 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7375981/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 Early cellular events in Parkinson’s disease (PD) remain elusive. While aggregation of α-synuclein (αSyn) into Lewy bodies marks advanced pathology, smaller αSyn oligomers have been implicated in prodromal stages. Here we map αSyn oligomers at single-particle resolution in post-mortem brain tissue from Braak stage 3/4 PD cases and matched controls. Quantitative imaging of 9,882 neurons across four regions captured over 112 million αSyn oligomers. Mean intracellular α-Syn burden was unchanged between groups, but PD samples contained a higher fraction of neurons whose oligomer load exceeded a specific aggregation threshold. We term these aggregation-susceptible cells (ASCs). ASC enrichment in vulnerable regions supports a population-level model in which early pathology arises from a stochastic shift in cellular composition rather than altered αSyn aggregation kinetics. This human-tissue, large-scale dataset provides a quantitative framework for detecting ASCs and for testing population-level interventions in PD and related proteinopathies. Biological sciences/Biophysics/Single-molecule biophysics Biological sciences/Cell biology/Cellular imaging Full Text Additional Declarations Yes there is potential Competing Interest. SFL is a cofounder and shareholder in ZOMP. Supplementary Files SISubmission.pdf Supplementary Information, α-Synuclein driven cell susceptibility in Parkinson’s disease 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-7375981","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":532826785,"identity":"396bccc5-ab19-4439-a461-16b574b971c1","order_by":0,"name":"Steven 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