OTUD5 Protects Dopaminergic Neurons by Promoting the Degradation of α-Synuclein in Parkinson's Disease Model
- Adv Sci (Weinh). 2024 Dec 25:e2406700. doi: 10.1002/advs.202406700.
- 1. Department of Pharmacology, School of Basic Medical Sciences, Shandong University, Jinan, Shandong, 250012, P. R. China.
- 2. Key Laboratory of Infection and Immunity of Shandong Province, School of Basic Medical Sciences, Shandong University, Jinan, Shandong, 250012, P. R. China.
- 3. Department of Immunology, School of Basic Medical Sciences, Shandong University, Jinan, Shandong, 250012, P. R. China.
- 4. Department of Rehabilitation Medicine, The Second Hospital, Shandong University, Jinan, Shandong, 250012, P. R. China.
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.