Neuronal FAM171A2 mediates α-synuclein fibril uptake and drives Parkinson’s disease

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

doi:10.1126/science.adp3645

Neuronal FAM171A2 mediates α-synuclein fibril uptake and drives Parkinson’s disease

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 LuWei 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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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.

Original language	English (US)
Pages (from-to)	892-900
Number of pages	9
Journal	Science
Volume	387
Issue number	6736
DOIs	https://doi.org/10.1126/science.adp3645
State	Published - Feb 21 2025

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Wu, K. M., Xu, Q. H., Liu, Y. Q., Feng, Y. W., Han, S. D., Zhang, Y. R., Chen, S. D., Guo, Y., Wu, B. S., Ma, L. Z., Zhang, Y., Chen, Y. L., Yang, L., Yang, Z. F., Xiao, Y. J., Wang, T. T., Zhao, J., Chen, S. F., Cui, M., ... Yu, J. T. (2025). Neuronal FAM171A2 mediates α-synuclein fibril uptake and drives Parkinson’s disease. Science, 387(6736), 892-900. https://doi.org/10.1126/science.adp3645

Wu, KM, Xu, QH, Liu, YQ, Feng, YW, Han, SD, Zhang, YR, Chen, SD, Guo, Y, Wu, BS, Ma, LZ, Zhang, Y, Chen, YL, Yang, L, Yang, ZF, Xiao, YJ, Wang, TT, Zhao, J, Chen, SF, Cui, M, Lu, BX, Le, WD, Shu, YS, Ye, K, Li, JY, Li, WS, Wang, J, Liu, C, Yuan, P & Yu, JT 2025, 'Neuronal FAM171A2 mediates α-synuclein fibril uptake and drives Parkinson’s disease', Science, vol. 387, no. 6736, pp. 892-900. https://doi.org/10.1126/science.adp3645

@article{dba33916f9164207a0a8fcfac7d0fece,

title = "Neuronal FAM171A2 mediates α-synuclein fibril uptake and drives Parkinson{\textquoteright}s disease",

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.",

author = "Wu, {Kai Min} and Xu, {Qian Hui} and Liu, {Yi Qi} and Feng, {Yi Wei} and Han, {Si Da} and Zhang, {Ya Ru} and Chen, {Shi Dong} and Yu Guo and Wu, {Bang Sheng} and Ma, {Ling Zhi} and Yi Zhang and Chen, {Yi Lin} and Liu Yang and Yang, {Zhao Fei} and Xiao, {Yu Jie} and Wang, {Ting Ting} and Jue Zhao and Chen, {Shu Fen} and Mei Cui and Lu, {Bo Xun} and Le, {Wei Dong} and Shu, {You Sheng} and Keqiang Ye and Li, {Jia Yi} and Li, {Wen Sheng} and Jian Wang and Cong Liu and Peng Yuan and Yu, {Jin Tai}",

year = "2025",

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doi = "10.1126/science.adp3645",

language = "English (US)",

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T1 - Neuronal FAM171A2 mediates α-synuclein fibril uptake and drives Parkinson’s disease

AU - Wu, Kai Min

AU - Xu, Qian Hui

AU - Liu, Yi Qi

AU - Feng, Yi Wei

AU - Han, Si Da

AU - Zhang, Ya Ru

AU - Chen, Shi Dong

AU - Guo, Yu

AU - Wu, Bang Sheng

AU - Ma, Ling Zhi

AU - Zhang, Yi

AU - Chen, Yi Lin

AU - Yang, Liu

AU - Yang, Zhao Fei

AU - Xiao, Yu Jie

AU - Wang, Ting Ting

AU - Zhao, Jue

AU - Chen, Shu Fen

AU - Cui, Mei

AU - Lu, Bo Xun

AU - Le, Wei Dong

AU - Shu, You Sheng

AU - Ye, Keqiang

AU - Li, Jia Yi

AU - Li, Wen Sheng

AU - Wang, Jian

AU - Liu, Cong

AU - Yuan, Peng

AU - Yu, Jin Tai

PY - 2025/2/21

Y1 - 2025/2/21

N2 - 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.

AB - 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.

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EP - 900

JO - Science

JF - Science

IS - 6736

ER -

Neuronal FAM171A2 mediates α-synuclein fibril uptake and drives Parkinson’s disease

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