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

Abstract

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.

• Authors: Juan F Reyes, Sara Ekmark-Léwen, Marina Perdiki, Therése Klingstedt, Alana Hoffmann, Emilia Wiechec, Per Nilsson, K Peter R Nilsson, Irina Alafuzoff, Martin Ingelsson, Martin Hallbeck
• Journal: Acta neuropathologica communications (Acta Neuropathol Commun) Vol. 9 Issue 1 Pg. 46 (03 20 2021) ISSN: 2051-5960 [Electronic] England
• PMID: 33743820 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• SNCA protein, human
• alpha-Synuclein

Topics

• Aged
• Aged, 80 and over
• Animals
• Brain (metabolism, pathology)
• Disease Models, Animal
• Female
• Humans
• Lewy Body Disease (metabolism, pathology, physiopathology)
• Liver (metabolism)
• Male
• Mice
• Mice, Transgenic
• Microscopy, Electron, Transmission
• Parkinson Disease (metabolism, pathology, physiopathology)
• Synucleinopathies (metabolism, pathology, physiopathology)
• alpha-Synuclein (metabolism)