OTUD5 Protects Dopaminergic Neurons by Promoting the Degradation of α-Synuclein in Parkinson's Disease Model

被引：0

作者：

Song, Xiaomeng ^{[1
]}

Liu, Tengfei ^{[1
]}

Yu, Lu ^{[1
]}

Ji, Qiuran ^{[1
]}

Guo, Xin ^{[1
]}

Zong, Runzhe ^{[1
]}

Li, Yiquan ^{[1
]}

Huang, Gan ^{[1
]}

Xue, Qidi ^{[1
]}

Fu, Qingyi ^{[1
]}

Liu, Bingyu ^{[2
,3
]}

Zheng, Yi ^{[2
,3
]}

Chen, Lin ^{[1
]}

Gao, Chengjiang ^{[2
,3
]}

Liu, Huiqing ^{[1
,4
]}

机构：

[1] Shandong Univ, Sch Basic Med Sci, Dept Pharmacol, Jinan 250012, Shandong, Peoples R China

[2] Shandong Univ, Sch Basic Med Sci, Key Lab Infect & Immun Shandong Prov, Jinan 250012, Shandong, Peoples R China

[3] Shandong Univ, Sch Basic Med Sci, Dept Immunol, Jinan 250012, Shandong, Peoples R China

[4] Shandong Univ, Hosp 2, Dept Rehabil Med, Jinan 250012, Shandong, Peoples R China

来源：

ADVANCED SCIENCE | 2025年 / 12卷 / 07期

基金：

中国国家自然科学基金;

关键词：

deubiquitinase; endolysosomal pathway; nedd4; otud5; parkinson's disease; alpha-synuclein; DEUBIQUITINASE; AUTOPHAGY; PATHWAYS; PROTEINS; SYSTEMS; BRAIN; DUBA;

D O I：

10.1002/advs.202406700

中图分类号：

O6 [化学];

学科分类号：

0703 ;

摘要：

Defective clearance and accumulation of alpha-synuclein (alpha-Syn) is the key pathogenic factor in Parkinson's disease (PD). Recent studies emphasize the importance of E3 ligases in regulating the degradation of alpha-Syn. However, the molecular mechanisms by which deubiquitinases regulate alpha-Syn degradation are scarcely studied. In this study, it is found that the protein levels of alpha-Syn are negatively regulated by ovarian tumor protease deubiquitinase 5 (OTUD5) which protects dopaminergic (DA) neurons in the PD model. Mechanistically, OTUD5 promotes K63-linked polyubiquitination of alpha-Syn independent of its deubiquitinating enzyme activity and mediates its endolysosomal degradation by recruiting the E3 ligase neural precursor cell expressed developmentally downregulated 4 (NEDD4). Furthermore, OTUD5 conditional knockout in DA neurons results in more severe alpha-Syn related pathology and dyskinesia after injection of alpha-Syn preformed fibrils (PFF). Overall, the data unveil a novel mechanism to regulate the degradation of alpha-Syn and provide a new therapeutic strategy to alleviate DA neurodegeneration.

引用

页数：15

共 62 条

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