Neuronal FAM171A2 mediates α-synuclein fibril uptake and drives Parkinson’s disease.
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| Title: | Neuronal FAM171A2 mediates α-synuclein fibril uptake and drives Parkinson’s disease. |
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| 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 |
| Source: | Science (pre-March 2025). 2/21/2025, Vol. 387 Issue 6736, p892-900. 9p. 5 Color Photographs. |
| Subjects: | Parkinson's disease, Binding site assay, Dopamine receptors |
| 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. [ABSTRACT FROM AUTHOR] |
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| Database: | Psychology and Behavioral Sciences Collection |
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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. [ABSTRACT FROM AUTHOR] |
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| ISSN: | 00368075 |
| DOI: | 10.1126/science.adp3645 |
