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The different phenotypic characteristics of the synucleinopathies Parkinson\u2019s disease (PD), Dementia with Lewy Bodies (DLB) and Multiple System Atrophy (MSA) have been proposed to originate from the distinct structures adopted by \u03b1Syn in its amyloid forms. Here, using covalent labeling and limited proteolysis coupled to mass spectrometry (LiP-MS) in vitro and in situ within neuronal cells and directly in native patient brain homogenates, we show that pathogenic \u03b1Syn from distinct synucleinopathies (PD, DLB and MSA) are structurally different. Further, we found that fibril structural differences are associated with different putative fibril interactomes and neuronal responses. We discovered disease-specific ubiquitination patterns and turnover profiles for pathogenic \u03b1Syn species, detected molecular pathways responding specifically to the uptake of different \u03b1Syn fibrillar polymorphs, and identified a subset of the involved proteins as putative interactors of \u03b1Syn. In particular, components of the ubiquitin-proteasomal System (UPS), including E3 ubiquitin ligases, chaperones, and deubiquitinating proteins, showed disease\/polymorph-specific putative interaction patterns, possibly accounting for different resistance of patient-derived \u03b1Syn fibrils to degradation. Genetic modulation with CRISPR-based tools showed that members of the UPS degradation pathway (three E3 ligases: UBE3A, TRIM25, HUWE1 and the AAA+ ATPase VCP) reduced \u03b1Syn inclusions, in a strain-specific manner. LiP-MS also identified sets of proteins with altered protease susceptibility in postmortem brain homogenates of PD, DLB, and MSA patients. These sets were largely disease-specific and included proteins altered in cells treated with fibrils derived from patients with the matching disease. Our findings provide insight into cellular processes involved in the accumulation and turnover of \u03b1Syn pathogenic aggregates in PD, DLB and MSA in a disease\/specific manner and constitutes a resource of potential novel drug targets in these synucleinopathies.<\/jats:p>","DOI":"10.1038\/s44320-026-00199-5","type":"journal-article","created":{"date-parts":[[2026,3,11]],"date-time":"2026-03-11T16:05:39Z","timestamp":1773245139000},"page":"868-901","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Structure-function relationship of alpha-synuclein fibrillar polymorphs derived from distinct synucleinopathies"],"prefix":"10.1038","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3706-5911","authenticated-orcid":false,"given":"Tetiana","family":"Serdiuk","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2694-8388","authenticated-orcid":false,"given":"Virginie","family":"Redeker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jimmy","family":"Savistchenko","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0677-8289","authenticated-orcid":false,"given":"Sandesh","family":"Neupane","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Walther","family":"Haenseler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanick","family":"Fleischmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7653-6918","authenticated-orcid":false,"given":"Viviane","family":"Reber","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8976-9208","authenticated-orcid":false,"given":"Sabrina","family":"Keller","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cinzia","family":"Tiberi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruxandra","family":"Bachmann-Gagescu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3245-3253","authenticated-orcid":false,"given":"Matthias","family":"Gstaiger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Braun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roland","family":"Riek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7131-4643","authenticated-orcid":false,"given":"Steve","family":"Gentleman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0344-6708","authenticated-orcid":false,"given":"Adriano","family":"Aguzzi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4286-8951","authenticated-orcid":false,"given":"Natalie","family":"de Souza","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0000-7096","authenticated-orcid":false,"given":"Ronald","family":"Melki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4109-3552","authenticated-orcid":false,"given":"Paola","family":"Picotti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,3,11]]},"reference":[{"key":"199_CR1","doi-asserted-by":"publisher","first-page":"552","DOI":"10.1038\/nrm2204","volume":"8","author":"A Aguzzi","year":"2007","unstructured":"Aguzzi A, Heikenwalder M, Polymenidou M (2007) Insights into prion strains and neurotoxicity. 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