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The contribution of <jats:italic>\u03b1<\/jats:italic>Syn cytopathologies to the pathogenesis of these diseases is underappreciated. Seed amplification assays of MSA and LBD brains have revealed striking differences in <jats:italic>\u03b1<\/jats:italic>Syn seeding between regions and cases. Therefore, our aim was to evaluate whether different brain regions containing distinct <jats:italic>\u03b1<\/jats:italic>Syn cytopathologies contribute to different seeding characteristics. We collected 2\u2010mm micro\u2010punches of regions in MSA (<jats:italic>n<\/jats:italic>\u2009=\u200910) and LBD (<jats:italic>n<\/jats:italic>\u2009=\u200915) cases from formalin\u2010fixed paraffin\u2010embedded tissues. We performed double immuno\u2010labeling for disease\u2010associated <jats:italic>\u03b1<\/jats:italic>Syn and cellular markers on tissue microarrays, evaluated co\u2010deposition of other neurodegenerative disease\u2010related proteins and, from the same micro\u2010punched samples, we analyzed <jats:italic>\u03b1<\/jats:italic>Syn seeding. Based on these variables, machine learning algorithms were used to reduce dimensionality of the dataset and cluster the regions in MSA and LBD cases, revealing that different compositions of <jats:italic>\u03b1<\/jats:italic>Syn cytopathologies influence <jats:italic>\u03b1<\/jats:italic>Syn seeding patterns. Our results support the notion of different cellular processing of <jats:italic>\u03b1<\/jats:italic>Syn and its contribution to the variability in seeding. This has implications for understanding disease progression, interpretation of seed amplification assays, and opens avenues for the development of cell type\u2010specific antibodies against <jats:italic>\u03b1<\/jats:italic>Syn.<\/jats:p>","DOI":"10.1111\/bpa.70024","type":"journal-article","created":{"date-parts":[[2025,6,17]],"date-time":"2025-06-17T01:59:34Z","timestamp":1750125574000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Contribution of <i>\u03b1<\/i>\u2010synuclein cytopathologies to distinct seeding of misfolded <i>\u03b1<\/i>\u2010synuclein"],"prefix":"10.1111","volume":"35","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-3810-6390","authenticated-orcid":false,"given":"Ain","family":"Kim","sequence":"first","affiliation":[{"name":"Department of Laboratory Medicine &amp; Pathobiology University of Toronto  Toronto Ontario Canada"},{"name":"Tanz Centre for Research in Neurodegenerative Disease University of Toronto  Toronto Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6463-6321","authenticated-orcid":false,"given":"Ivan","family":"Martinez\u2010Valbuena","sequence":"additional","affiliation":[{"name":"Tanz Centre for Research in Neurodegenerative Disease University of Toronto  Toronto Ontario Canada"},{"name":"Krembil Brain Institute, University Health Network  Toronto Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Krisztina","family":"Danics","sequence":"additional","affiliation":[{"name":"Department of Forensic and Insurance Medicine Semmelweis University  Budapest Hungary"},{"name":"Neuropathology and Prion Disease Reference Center, Department of Forensic and Insurance Medicine Semmelweis University  Budapest Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7863-5389","authenticated-orcid":false,"given":"Shelley L.","family":"Forrest","sequence":"additional","affiliation":[{"name":"Tanz Centre for Research in Neurodegenerative Disease University of Toronto  Toronto Ontario Canada"},{"name":"Krembil Brain Institute, University Health Network  Toronto Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3841-5511","authenticated-orcid":false,"given":"Gabor G.","family":"Kovacs","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine &amp; Pathobiology University of Toronto  Toronto Ontario Canada"},{"name":"Tanz Centre for Research in Neurodegenerative Disease University of Toronto  Toronto Ontario Canada"},{"name":"Krembil Brain Institute, University Health Network  Toronto Ontario Canada"},{"name":"Neuropathology and Prion Disease Reference Center, Department of Forensic and Insurance Medicine Semmelweis University  Budapest Hungary"},{"name":"Edmond J. 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