Science (New York, N.Y.) · 2025
Neuronal FAM171A2 mediates α-synuclein fibril uptake and drives Parkinson's disease.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод пока не подготовлен
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Wu Kai-Min, Xu Qian-Hui, Liu Yi-Qi, Feng Yi-Wei, Han Si-Da, Zhang Ya-Ru, Chen Shi-Dong, Guo Yu, Wu Bang-Sheng, Ma Ling-Zhi, Zhang Yi, Chen Yi-Lin, Yang Liu, Yang Zhao-Fei, Xiao Yu-Jie, Wang Ting-Ting, Zhao Jue, Chen Shu-Fen, Cui Mei, Lu Bo-Xun, Le Wei-Dong, Shu You-Sheng, Ye Keqiang, Li Jia-Yi, Li Wen-Sheng, Wang Jian, Liu Cong, Yuan Peng, Yu Jin-Tai
Аннотация
Neuronal accumulation and spread of pathological α-synuclein (α-syn) fibrils are key events in Parkinson's disease (PD) pathophysiology. However, the neuronal mechanisms underlying the uptake of α-syn fibrils remain unclear. In this work, we identified FAM171A2 as a PD risk gene that affects α-syn aggregation. Overexpressing FAM171A2 promotes α-syn fibril endocytosis and exacerbates the spread and neurotoxicity of α-syn pathology. Neuronal-specific knockdown of FAM171A2 expression shows protective effects. Mechanistically, the FAM171A2 extracellular domain 1 interacts with the α-syn C terminus through electrostatic forces, with >1000 times more selective for fibrils. Furthermore, we identified bemcentinib as an effective blocker of FAM171A2-α-syn fibril interaction with an in vitro binding assay, in cellular models, and in mice. Our findings identified FAM171A2 as a potential receptor for the neuronal uptake of α-syn fibrils and, thus, as a therapeutic target against PD.