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The pathological hallmark of MSA is the progressive accumulation of glial cytoplasmic inclusions (GCIs) in oligodendrocytes that are comprised of \u03b1-synuclein (\u03b1Syn) aberrantly polymerized into fibrils. Experimentally, MSA brain samples display a high level of seeding activity to induce further \u03b1Syn aggregation by a prion-like conformational mechanism. Paradoxically, \u03b1Syn is predominantly a neuronal brain protein, with only marginal levels expressed in normal or diseased oligodendrocytes, and \u03b1Syn inclusions in other neurodegenerative diseases, including Parkinson\u2019s disease and Dementia with Lewy bodies, are primarily found in neurons. Although GCIs are the hallmark of MSA, using a series of new monoclonal antibodies targeting the carboxy-terminal region of \u03b1Syn, we demonstrate that neuronal \u03b1Syn pathology in MSA patient brains is remarkably abundant in the pontine nuclei and medullary inferior olivary nucleus. This neuronal \u03b1Syn pathology has distinct histological properties compared to GCIs, which allows it to remain concealed to many routine detection methods associated with altered biochemical properties of the carboxy-terminal domain of \u03b1Syn. We propose that these previously underappreciated sources of aberrant \u03b1Syn could serve as a pool of \u03b1Syn prion seeds that can initiate and continue to drive the pathogenesis of MSA.<\/jats:p>","DOI":"10.1186\/s40478-021-01173-y","type":"journal-article","created":{"date-parts":[[2021,5,3]],"date-time":"2021-05-03T06:03:10Z","timestamp":1620021790000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":28,"title":["Robust \u03b1-synuclein pathology in select brainstem neuronal populations is a potential instigator of multiple system atrophy"],"prefix":"10.1186","volume":"9","author":[{"given":"Ethan W.","family":"Hass","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zachary A.","family":"Sorrentino","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Grace M.","family":"Lloyd","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nikolaus R.","family":"McFarland","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan","family":"Prokop","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2992-4234","authenticated-orcid":false,"given":"Benoit I.","family":"Giasson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,5,3]]},"reference":[{"key":"1173_CR1","doi-asserted-by":"publisher","first-page":"249","DOI":"10.1056\/NEJMra1311488","volume":"372","author":"A Fanciulli","year":"2015","unstructured":"Fanciulli A, Wenning GK (2015) Multiple-system atrophy. 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