Neuronal FAM171A2 mediates α-synuclein fibril uptake and drives Parkinson’s disease
Kaimin Wu, Qianhui Xu, Yiqi Liu, Yiwei Feng, Sida Han, Ya-Ru Zhang, Shi-Dong Chen, Yu Guo, Bang‐Sheng Wu, Lingzhi Ma, Yi Zhang, Yilin Chen, Yang Liu, Zhaofei Yang, Yujie Xiao, Tingting Wang, Jue Zhao, Shu-Fen Chen, Mei Cui, Boxun Lu, Weidong Le, Yousheng Shu, Keqiang Ye, Jiayi Li, Wensheng Li, Jian Wang, Cong Liu, Peng Yuan, Jin‐Tai Yu
Abstract
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.