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

Abstract Defective clearance and accumulation of α‐synuclein (α‐Syn) is the key pathogenic factor in Parkinson's disease (PD). Recent studies emphasize the importance of E3 ligases in regulating the degradation of α‐Syn. However, the molecular mechanisms by which deubiquitinases regulate α‐Syn degradation are scarcely studied. In this study, it is found that the protein levels of α‐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 α‐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 α‐Syn related pathology and dyskinesia after injection of α‐Syn preformed fibrils (PFF). Overall, the data unveil a novel mechanism to regulate the degradation of α‐Syn and provide a new therapeutic strategy to alleviate DA neurodegeneration.