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Aggregates of alpha-synuclein (\u03b1syn) phosphorylated at serine 129 (PSER129) are hallmarks of synucleinopathies, which, for PD\/DLB, are found predominantly in neurons, whereas in MSA, aggregates are primarily found in oligodendroglia. It remains unclear whether the distinct pathological presentations of PD\/DLB and MSA are manifestations of unique or shared pathological processes. Using the in-situ proximity labeling technique of biotinylation by antibody recognition (BAR), we compared aggregated \u03b1syn-interactomes (BAR-PSER129) and total \u03b1syn-interactomes (BAR-MJFR1) between MSA (n\u2009=\u20095) and PD\/DLB (n\u2009=\u200910) in forebrain and midbrain structures. Comparison between MSA and PD\/DLB-enriched proteins revealed 79 PD\/DLB-differentially abundant proteins and only three MSA-differentially abundant proteins (CBR1, CRYAB, and GFAP). Pathway enrichment analysis revealed that vesicle\/SNARE-associated pathways dominated PD\/DLB interactions, whereas MSA was strongly enriched for metabolic\/catabolic, iron, and cellular oxidant detoxification pathways. A subnetwork of cytosolic antioxidant enzymes called peroxiredoxins drove cellular detoxification pathway enrichment in MSA. A network of 26 proteins, including neuronal-specific proteins (e.g., SYNGR3) with HSPA8 at the core, was shared between MSA and DLB\/PD. Extracellular exosome pathways were universally enriched regardless of the disease or BAR target protein. In conclusion, synucleinopathies have divergent and convergent \u03b1syn-aggregate interactions, indicating unique and shared pathogenic mechanisms. MSA uniquely involves oxidant detoxification processes in glial cells, while vesicular processes in neurons dominate PD\/DLB. Shared interactions, specifically SYNGR3, between MSA and PD\/DLB suggest that neuronal axons are the origin of both diseases. In conclusion, we provide \u03b1syn protein interaction maps for two distinct synucleinopathies.<\/jats:p>","DOI":"10.1186\/s40478-025-01958-5","type":"journal-article","created":{"date-parts":[[2025,3,23]],"date-time":"2025-03-23T20:19:07Z","timestamp":1742761147000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Proximity proteomics reveals unique and shared pathological features between multiple system atrophy and Parkinson\u2019s disease"],"prefix":"10.1186","volume":"13","author":[{"given":"Solji G.","family":"Choi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tyler R.","family":"Tittle","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raj R.","family":"Barot","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dakota J.","family":"Betts","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johnie J.","family":"Gallagher","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey H.","family":"Kordower","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yaping","family":"Chu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bryan A.","family":"Killinger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,3,23]]},"reference":[{"key":"1958_CR1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbc.2022.102343","volume":"298","author":"M Artan","year":"2022","unstructured":"Artan M, Hartl M, Chen W, de Bono M (2022) Depletion of endogenously biotinylated carboxylases enhances the sensitivity of turboID-mediated proximity labeling in caenorhabditis elegans. 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