神经元FAM171A2介导α-突触核蛋白原纤维摄取并驱动帕金森病，这一成果由复旦大学
在这项工作中，小组发现FAM171A2是一个影响α-syn聚集的PD风险基因。过表达FAM171A2促进α-syn纤维内吞，加剧α-syn病理的扩散和神经毒性。神经元特异性敲低FAM171A2表达具有保护作用。机制上，FAM171A2胞外结构域1通过静电力与α-syn C末端相互作用，对原纤维的选择性高1000倍。
此外，通过体外结合实验、细胞模型和小鼠实验，该研究组发现bmcentinib是FAM171A2 -α-syn纤维相互作用的有效阻断剂。他们的研究发现FAM171A2是神经元摄取α-syn原纤维的潜在受体，并且是治疗PD的靶点。
据介绍，病理性α-突触核蛋白（α-syn）原纤维的神经元积累和扩散是帕金森病（PD）病理生理的关键事件。然而，α-syn原纤维摄取的神经元机制尚不清楚。
附：英文原文
Title: Neuronal FAM171A2 mediates α-synuclein fibril uptake and drives Parkinson’s disease
Author: Kai-Min Wu, Qian-Hui Xu, Yi-Qi Liu, Yi-Wei Feng, Si-Da Han, Ya-Ru Zhang, Shi-Dong Chen, Yu Guo, Bang-Sheng Wu, Ling-Zhi Ma, Yi Zhang, Yi-Lin Chen, Liu Yang, Zhao-Fei Yang, Yu-Jie Xiao, Ting-Ting Wang, Jue Zhao, Shu-Fen Chen, Mei Cui, Bo-Xun Lu, Wei-Dong Le, You-Sheng Shu, Keqiang Ye, Jia-Yi Li, Wen-Sheng Li, Jian Wang, Cong Liu, Peng Yuan, Jin-Tai Yu
Issue&Volume: 2025-02-21
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.
DOI: adp3645
Source: https://www.science.org/doi/10.1126/science.adp3645