| Title: | Neuronal FAM171A2 mediates α-synuclein fibril uptake and drives Parkinson's disease |
| Journal: | Science |
| Published: | 20 Feb 2025 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/39977508/ |
| DOI: | https://doi.org/10.1126/science.adp3645 |
Publication 15314
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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.</p>
10 Keywords
- Animals
- Endocytosis
- Gene Knockdown Techniques
- Humans
- Mice
- Neurons
- Parkinson Disease
- Protein Aggregation, Pathological
- Static Electricity
- alpha-Synuclein
29 Authors
- 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
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