The deubiquitinase OTUD1 aggravated dopaminergic neurodegeneration in Parkinson's disease model by promoting the degradation of Parkin.

Abstract

Parkin plays a pivotal role in the pathogenesis of Parkinson's disease (PD). Deubiquitinating enzymes (DUBs), which reverse Parkin ubiquitination, are critical for maintaining mitochondrial homeostasis. Although ovarian tumor protease deubiquitinase 1 (OTUD1) participates in various biological processes, its specific functions in PD and its regulation of Parkin remain unclear. In this study, we demonstrated that OTUD1 expression was significantly elevated in the nigrostriatal region of PD patients and MPTP-induced PD mice. Genetic ablation of OTUD1 markedly improved motor deficits and attenuated dopaminergic neuronal loss in PD models. Mechanistically, OTUD1 worsened mitochondrial dysfunction in PD models by negatively regulating Parkin protein levels. OTUD1 interacted with Parkin and selectively removed K27- and K33-linked polyubiquitin chains through its DUB activity, leading to Parkin degradation via the autophagic-lysosomal pathway. Our findings identify OTUD1 as a negative regulator of Parkin and reveal a mechanism linking deubiquitination to mitochondrial dysfunction in PD, which offers a novel potential therapeutic target for PD.