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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.
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]
Copyright of Science (pre-March 2025) is the property of American Association for the Advancement of Science and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
Database: Psychology and Behavioral Sciences Collection
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PubType: Academic Journal
PubTypeId: academicJournal
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  Label: Title
  Group: Ti
  Data: Neuronal FAM171A2 mediates α-synuclein fibril uptake and drives Parkinson’s disease.
– Name: Author
  Label: Authors
  Group: Au
  Data: <searchLink fieldCode="AR" term="%22Kai-Min+Wu%22">Kai-Min Wu</searchLink><br /><searchLink fieldCode="AR" term="%22Qian-Hui+Xu%22">Qian-Hui Xu</searchLink><br /><searchLink fieldCode="AR" term="%22Yi-Qi+Liu%22">Yi-Qi Liu</searchLink><br /><searchLink fieldCode="AR" term="%22Yi-Wei+Feng%22">Yi-Wei Feng</searchLink><br /><searchLink fieldCode="AR" term="%22Si-Da+Han%22">Si-Da Han</searchLink><br /><searchLink fieldCode="AR" term="%22Ya-Ru+Zhang%22">Ya-Ru Zhang</searchLink><br /><searchLink fieldCode="AR" term="%22Shi-Dong+Chen%22">Shi-Dong Chen</searchLink><br /><searchLink fieldCode="AR" term="%22Yu+Guo%22">Yu Guo</searchLink><br /><searchLink fieldCode="AR" term="%22Bang-Sheng+Wu%22">Bang-Sheng Wu</searchLink><br /><searchLink fieldCode="AR" term="%22Ling-Zhi+Ma%22">Ling-Zhi Ma</searchLink><br /><searchLink fieldCode="AR" term="%22Yi+Zhang%22">Yi Zhang</searchLink><br /><searchLink fieldCode="AR" term="%22Yi-Lin+Chen%22">Yi-Lin Chen</searchLink><br /><searchLink fieldCode="AR" term="%22Liu+Yang%22">Liu Yang</searchLink><br /><searchLink fieldCode="AR" term="%22Zhao-Fei+Yang%22">Zhao-Fei Yang</searchLink><br /><searchLink fieldCode="AR" term="%22Yu-Jie+Xiao%22">Yu-Jie Xiao</searchLink><br /><searchLink fieldCode="AR" term="%22Ting-Ting+Wang%22">Ting-Ting Wang</searchLink><br /><searchLink fieldCode="AR" term="%22Jue+Zhao%22">Jue Zhao</searchLink><br /><searchLink fieldCode="AR" term="%22Shu-Fen+Chen%22">Shu-Fen Chen</searchLink><br /><searchLink fieldCode="AR" term="%22Mei+Cui%22">Mei Cui</searchLink><br /><searchLink fieldCode="AR" term="%22Bo-Xun+Lu%22">Bo-Xun Lu</searchLink>
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  Data: <searchLink fieldCode="JN" term="%22Science+%28pre-March+2025%29%22">Science (pre-March 2025)</searchLink>. 2/21/2025, Vol. 387 Issue 6736, p892-900. 9p. 5 Color Photographs.
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  Label: Subjects
  Group: Su
  Data: <searchLink fieldCode="DE" term="%22Parkinson's+disease%22">Parkinson's disease</searchLink><br /><searchLink fieldCode="DE" term="%22Binding+site+assay%22">Binding site assay</searchLink><br /><searchLink fieldCode="DE" term="%22Dopamine+receptors%22">Dopamine receptors</searchLink>
– Name: Abstract
  Label: Abstract
  Group: Ab
  Data: 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]
– Name: AbstractSuppliedCopyright
  Label:
  Group: Ab
  Data: <i>Copyright of Science (pre-March 2025) is the property of American Association for the Advancement of Science and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.)
PLink https://search.ebscohost.com/login.aspx?direct=true&site=eds-live&db=pbh&AN=183182445
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              Text: 2/21/2025
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