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Polymorphic USP8 allele promotes Parkinson's disease by inducing the accumulation of α-synuclein through deubiquitination.
Wu, Shouhai; Lin, Tongxiang; Xu, Yang.
Afiliação
  • Wu S; State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China.
  • Lin T; Center for Regenerative and Translational Medicine, Guangdong Provincial Academy of Chinese Medical Sciences, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China.
  • Xu Y; Center for Regenerative and Translational Medicine, Guangdong Provincial Academy of Chinese Medical Sciences, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China.
Cell Mol Life Sci ; 80(12): 363, 2023 Nov 19.
Article em En | MEDLINE | ID: mdl-37981592
ABSTRACT
Parkinson's disease (PD) is one of the most common neuro-degenerative diseases characterized by α-synuclein accumulation and degeneration of dopaminergic neurons. Employing genome-wide sequencing, we identified a polymorphic USP8 allele (USP8D442G) significantly enriched in Chinese PD patients. To test the involvement of this polymorphism in PD pathogenesis, we derived dopaminergic neurons (DAn) from human-induced pluripotent stem cells (hiPSCs) reprogrammed from fibroblasts of PD patients harboring USP8D442G allele and their healthy siblings. In addition, we knock-in D442G polymorphic site into the endogenous USP8 gene of human embryonic stem cells (hESCs) and derived DAn from these knock-in hESCs to explore their cellular phenotypes and molecular mechanism. We found that expression of USP8D442G in DAn induces the accumulation and abnormal subcellular localization of α-Synuclein (α-Syn). Mechanistically, we demonstrate that D442G polymorphism enhances the interaction between α-Syn and USP8 and thus increases the K63-specific deubiquitination and stability of α-Syn . We discover a pathogenic polymorphism for PD that represent a promising therapeutic and diagnostic target for PD.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Doença de Parkinson Limite: Humans Idioma: En Revista: Cell Mol Life Sci Assunto da revista: BIOLOGIA MOLECULAR Ano de publicação: 2023 Tipo de documento: Article País de afiliação: China

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Doença de Parkinson Limite: Humans Idioma: En Revista: Cell Mol Life Sci Assunto da revista: BIOLOGIA MOLECULAR Ano de publicação: 2023 Tipo de documento: Article País de afiliação: China