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

Wu, Kai-Min ; Xu, Qian-Hui ; Liu, Yi-Qi ; Feng, Yi-Wei ; Han, Si-Da ; Zhang, Ya-Ru ; Chen, Shi-Dong ; Guo, Yu ; Wu, Bang-Sheng and Ma, Ling-Zhi , et al. (2025) In Science (New York, N.Y.) 387(6736). p.892-900
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... (More)

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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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Animals, Humans, Mice, alpha-Synuclein/metabolism, Amyloid/metabolism, Endocytosis, Neurons/metabolism, Parkinson Disease/genetics, Protein Aggregation, Pathological/metabolism, Membrane Proteins/genetics, Adaptor Proteins, Signal Transducing/genetics, Benzocycloheptenes/pharmacology, Triazoles/pharmacology
in
Science (New York, N.Y.)
volume
387
issue
6736
pages
892 - 900
publisher
American Association for the Advancement of Science (AAAS)
external identifiers
  • scopus:85219217505
  • pmid:39977508
ISSN
1095-9203
DOI
10.1126/science.adp3645
language
English
LU publication?
yes
id
93927075-76a2-4cd2-ac38-f42fcf4dcb68
date added to LUP
2025-10-03 13:46:35
date last changed
2025-10-04 04:08:34
@article{93927075-76a2-4cd2-ac38-f42fcf4dcb68,
  abstract     = {{<p>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 &gt;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>}},
  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 Guo, Yu and Wu, Bang-Sheng and Ma, Ling-Zhi and Zhang, Yi and Chen, Yi-Lin and Yang, Liu and Yang, Zhao-Fei and Xiao, Yu-Jie and Wang, Ting-Ting and Zhao, Jue and Chen, Shu-Fen and Cui, Mei and Lu, Bo-Xun and Le, Wei-Dong and Shu, You-Sheng and Ye, Keqiang and Li, Jia-Yi and Li, Wen-Sheng and Wang, Jian and Liu, Cong and Yuan, Peng and Yu, Jin-Tai}},
  issn         = {{1095-9203}},
  keywords     = {{Animals; Humans; Mice; alpha-Synuclein/metabolism; Amyloid/metabolism; Endocytosis; Neurons/metabolism; Parkinson Disease/genetics; Protein Aggregation, Pathological/metabolism; Membrane Proteins/genetics; Adaptor Proteins, Signal Transducing/genetics; Benzocycloheptenes/pharmacology; Triazoles/pharmacology}},
  language     = {{eng}},
  month        = {{02}},
  number       = {{6736}},
  pages        = {{892--900}},
  publisher    = {{American Association for the Advancement of Science (AAAS)}},
  series       = {{Science (New York, N.Y.)}},
  title        = {{Neuronal FAM171A2 mediates α-synuclein fibril uptake and drives Parkinson's disease}},
  url          = {{http://dx.doi.org/10.1126/science.adp3645}},
  doi          = {{10.1126/science.adp3645}},
  volume       = {{387}},
  year         = {{2025}},
}