1. α-Synuclein Degradation in Brain Pericytes Is Mediated via Akt, ERK, and p38 MAPK Signaling Pathways.
- Author
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Yokoya, Miki, Takata, Fuyuko, Iwao, Takuro, Matsumoto, Junichi, Tanaka, Yasuyoshi, Aridome, Hisataka, Yasunaga, Miho, Mizoguchi, Junko, Sano, Kazunori, and Dohgu, Shinya
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CATHEPSIN D ,PARKINSON'S disease ,ENDOTHELIAL cells ,PERICYTES ,PROTEASOME inhibitors - Abstract
Parkinson's disease (PD) is characterized by widespread distribution of Lewy bodies, which are composed of phosphorylated and aggregated forms of α-Synuclein (α-Syn), in the brain. Although the accumulation and propagation of α-Syn contribute to the development of PD, the involvement of the blood–brain barrier (BBB) in these processes remains unknown. Pericytes, one of the cell types that constitute the BBB, degrade various forms of α-Syn. However, the detailed mechanisms involved in α-Syn degradation by pericytes remain poorly understood. Therefore, in this study, we aimed to determine the ability of the BBB-constituting cells, particularly primary cultures of rat pericytes, brain endothelial cells, and astrocytes, to degrade α-Syn. After α-Syn uptake by the cells, intracellular α-Syn decreased only in pericytes. This pericyte-specific α-Syn decrease was inhibited by an autophagy inhibitor, bafilomycin A1, and a proteasome inhibitor, MG132. siRNA-mediated knockdown of degradation enzymes or familial PD-associated genes, including cathepsin D, DJ-1, and LRRK2, did not affect α-Syn clearance in pericytes. However, pharmacological inhibitors of Akt, ERK, and p38 MAPK inhibited α-Syn degradation by pericytes. In conclusion, our results suggest that α-Syn degradation by pericytes is mediated by an autophagy–lysosome system and a ubiquitin–proteasome system via α-Syn-activated Akt, ERK, and p38 MAPK signaling pathways. [ABSTRACT FROM AUTHOR]
- Published
- 2025
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