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Accumulation of alpha-synuclein within the liver, potential role in the clearance of brain pathology associated with Parkinson's disease

Reyes JF, Ekmark-Lewen S, Perdiki M, Klingstedt T, Hoffmann A, Wiechec E, Nilsson P, Nilsson KPR, Alafuzoff I, Ingelsson M, Hallbeck M (2021)

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Publication Type: Journal article

Publication year: 2021

Journal

Book Volume: 9

Journal Issue: 1

DOI: 10.1186/s40478-021-01136-3

Abstract

Alpha-synuclein (alpha-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 alpha-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 alpha-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 alpha-syn assemblies mediated, at least in part, by the gap junction protein connexin-32 (Cx32). Moreover, we identified a time-dependent accumulation of alpha-syn within the liver of three different transgenic (tg) mouse models expressing human alpha-syn under CNS-specific promoters, despite the lack of alpha-syn mRNA expression within the liver. Such a brain-to-liver transmission route could be further corroborated by detection of alpha-syn pathology within the liver of wild type mice one month after a single striatal alpha-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 alpha-syn pathology containing alpha-syn within hepatocellular structures to a higher degree (75%) than control subjects without alpha-syn accumulation in the brain (57%). Our results reveal that alpha-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.

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How to cite

APA:

Reyes, J.F., Ekmark-Lewen, S., Perdiki, M., Klingstedt, T., Hoffmann, A., Wiechec, E.,... Hallbeck, M. (2021). Accumulation of alpha-synuclein within the liver, potential role in the clearance of brain pathology associated with Parkinson's disease. Acta Neuropathologica Communications, 9(1). https://doi.org/10.1186/s40478-021-01136-3

MLA:

Reyes, Juan F., et al. "Accumulation of alpha-synuclein within the liver, potential role in the clearance of brain pathology associated with Parkinson's disease." Acta Neuropathologica Communications 9.1 (2021).

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