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It has been shown that familial PD-associated missense mutations within the \u03b1-synuclein gene destabilize the conformer equilibrium of physiologic \u03b1-synuclein in favor of unfolded monomers. Here, we characterized the relative levels of unfolded and helical forms of cytosolic \u03b1-synuclein in post-mortem human brain tissue and showed that the equilibrium of \u03b1-synuclein conformations is destabilized in sporadic PD and DLB patients. This disturbed equilibrium is decreased in a brain region-specific manner in patient samples pointing toward a possible \u201cprion-like\u201d propagation of the underlying pathology and forms distinct disease-specific patterns in the two different synucleinopathies. We are also able to show that a destabilization of multimers mechanistically leads to increased levels of insoluble, pathological \u03b1-synuclein, while pharmacological stabilization of multimers leads to a \u201cprion-like\u201d aggregation resistance. Together, our findings suggest that these disease-specific patterns of \u03b1-synuclein multimer destabilization in sporadic PD and DLB are caused by both regional neuronal vulnerability and \u201cprion-like\u201d aggregation transmission enabled by the destabilization of local endogenous \u03b1-synuclein protein.<\/jats:p>","DOI":"10.1007\/s00401-022-02406-7","type":"journal-article","created":{"date-parts":[[2022,2,9]],"date-time":"2022-02-09T22:02:26Z","timestamp":1644444146000},"page":"453-469","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":31,"title":["Brain region-specific susceptibility of Lewy body pathology in synucleinopathies is governed by \u03b1-synuclein conformations"],"prefix":"10.1007","volume":"143","author":[{"given":"Laura","family":"de Boni","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aurelia Hays","family":"Watson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ludovica","family":"Zaccagnini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amber","family":"Wallis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristina","family":"Zhelcheska","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nora","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Sanderson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haiyang","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elodie","family":"Martin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adam","family":"Cantlon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matteo","family":"Rovere","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marc","family":"Sylvester","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tammaryn","family":"Lashley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ulf","family":"Dettmer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zane","family":"Jaunmuktane","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4071-5612","authenticated-orcid":false,"given":"Tim","family":"Bartels","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,2,9]]},"reference":[{"key":"2406_CR1","doi-asserted-by":"publisher","first-page":"681","DOI":"10.1007\/s00401-019-02010-2","volume":"138","author":"J Alegre-Abarrategui","year":"2019","unstructured":"Alegre-Abarrategui J, Brimblecombe KR, Roberts RF, Velentza-Almpani E, Tilley BS, Bengoa-Vergniory N et al (2019) Selective vulnerability in \u03b1-synucleinopathies. 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