TY - JOUR AU - Reyes, Juan F. AU - Ekmark-Léwen, Sara AU - Perdiki, Marina AU - Klingstedt, Therése AU - Hoffmann, Alana AU - Wiechec, Emilia AU - Nilsson, Per AU - Nilsson, K. Peter R. AU - Alafuzoff, Irina AU - Ingelsson, Martin AU - Hallbeck, Martin PY - 2021 DA - 2021/03/20 TI - Accumulation of alpha-synuclein within the liver, potential role in the clearance of brain pathology associated with Parkinson’s disease JO - Acta Neuropathologica Communications SP - 46 VL - 9 IS - 1 AB - Alpha-synuclein (α-syn) aggregation is the hallmark pathological lesion in brains of patients with Parkinson’s disease (PD) and related neurological disorders characterized as synucleinopathies. Accumulating evidence now indicates that α-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 α-syn pathology also accumulates within the liver, the main organ responsible for substance clearance and detoxification. We further demonstrate that cultured human hepatocytes readily internalize oligomeric α-syn assemblies mediated, at least in part, by the gap junction protein connexin-32 (Cx32). Moreover, we identified a time-dependent accumulation of α-syn within the liver of three different transgenic (tg) mouse models expressing human α-syn under CNS-specific promoters, despite the lack of α-syn mRNA expression within the liver. Such a brain-to-liver transmission route could be further corroborated by detection of α-syn pathology within the liver of wild type mice one month after a single striatal α-syn injection. In contrast to the synucleinopathy models, aged mice modeling AD rarely show any amyloid-beta (Aß) deposition within the liver. In human post-mortem liver tissue, we identified cases with neuropathologically confirmed α-syn pathology containing α-syn within hepatocellular structures to a higher degree (75%) than control subjects without α-syn accumulation in the brain (57%). Our results reveal that α-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. SN - 2051-5960 UR - https://doi.org/10.1186/s40478-021-01136-3 DO - 10.1186/s40478-021-01136-3 ID - Reyes2021 ER -