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Accumulating evidence now indicates that \u03b1-syn deposition is also present within the gut and other peripheral organs outside the central nervous system (CNS). In the current study, we demonstrate for the first time that \u03b1-syn pathology also accumulates within the liver, the main organ responsible for substance\u00a0clearance and detoxification. We further demonstrate that cultured human hepatocytes readily internalize oligomeric \u03b1-syn assemblies mediated, at least in part, by the gap junction protein connexin-32 (Cx32). Moreover, we identified a time-dependent accumulation of \u03b1-syn within the liver of three different transgenic (tg)\u00a0mouse models expressing human \u03b1-syn under CNS-specific promoters, despite the lack of \u03b1-syn mRNA expression within the liver. Such a brain-to-liver transmission route could be further corroborated by detection of \u03b1-syn pathology within the liver of wild type mice one month after a single striatal \u03b1-syn injection. In contrast to the synucleinopathy models, aged mice modeling AD rarely show any amyloid-beta (A\u00df) deposition within the liver. In human post-mortem liver tissue, we identified cases with neuropathologically confirmed \u03b1-syn pathology containing \u03b1-syn within hepatocellular structures to a higher degree (75%) than control subjects without \u03b1-syn accumulation in the brain (57%). Our results reveal that \u03b1-syn accumulates within the liver and may be derived from the brain or other peripheral sources. Collectively, our findings indicate that the liver may play a role in the clearance and detoxification of pathological proteins in PD and related synucleinopathies.<\/jats:p>","DOI":"10.1186\/s40478-021-01136-3","type":"journal-article","created":{"date-parts":[[2021,3,20]],"date-time":"2021-03-20T08:02:54Z","timestamp":1616227374000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":60,"title":["Accumulation of alpha-synuclein within the liver, potential role in the clearance of brain pathology associated with Parkinson\u2019s disease"],"prefix":"10.1186","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6361-534X","authenticated-orcid":false,"given":"Juan F.","family":"Reyes","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Ekmark-L\u00e9wen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marina","family":"Perdiki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ther\u00e9se","family":"Klingstedt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alana","family":"Hoffmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emilia","family":"Wiechec","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Per","family":"Nilsson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"K. 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