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- Reyes, Juan, et al.
(författare)
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Accumulation of alpha-synuclein within the liver, potential role in the clearance of brain pathology associated with Parkinsons disease
- 2021
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Ingår i: Acta neuropathologica communications. - : BMC. - 2051-5960. ; 9:1
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Tidskriftsartikel (refereegranskat)abstract
- Alpha-synuclein (alpha-syn) aggregation is the hallmark pathological lesion in brains of patients with Parkinsons 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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| 2. |
- Reyes, Juan, et al.
(författare)
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Binding of alfa-synuclein oligomers to Cx32 facilitates protein uptake and transfer in neurons and oligodendrocytes
- 2019
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Ingår i: Acta Neuropathologica. - : SPRINGER. - 0001-6322 .- 1432-0533. ; 138:1, s. 23-47
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Tidskriftsartikel (refereegranskat)abstract
- The intercellular transfer of alpha-synuclein (-syn) has been implicated in the progression of Parkinson's disease (PD) and multiple system atrophy (MSA). The cellular mechanisms underlying this process are now beginning to be elucidated. In this study, we demonstrate that the gap junction protein connexin-32 (Cx32) is centrally involved in the preferential uptake of -syn oligomeric assemblies (o-syn) in neurons and oligodendrocytes. In vitro, we demonstrate a clear correlation between Cx32 expression and o-syn uptake. Pharmacological and genetic strategies targeting Cx32 successfully blocked o-syn uptake. In cellular and transgenic mice modeling PD and MSA, we observed significant upregulation of Cx32 which correlates with -syn accumulation. Notably, we could alsodemonstrate a direct interaction between -syn and Cx32 in two out of four human PD cases that was absent in all four age-matched controls. These data are suggestive of a link between Cx32 and PD pathophysiology. Collectively, our results provide compelling evidence for Cx32 as a novel target for therapeutic intervention in PD and related -synucleinopathies.
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