YOD1 regulates oxidative damage of dopamine neurons in Parkinson's disease by deubiquitinating PKM2

Abstract Background Parkinson's disease (PD) is a common neurodegenerative movement disorder, mainly characterized by the degeneration and loss of dopaminergic neurons in the substantia nigra. Oxidative stress is considered to be a key contributor to dopaminergic neuronal degeneration, triggering a series of downstream events such as mitochondrial dysfunction, neuroinflammation and misfolded protein aggregation, which ultimately exacerbate the development of PD. Deubiquitinating enzymes (DUBs) regulate oxidative stress, but their roles in PD remain unclear. Methods GEO database analysis and western blotting were used to analyze the expression of YOD1in PD patients and PD mouse models. Genetic knockout (KO) of YOD1 was performed to assess its effects in PD pathogenesis. The substance of YOD1 was measured via co‐immunoprecipitation (Co‐IP) coupled with LC‐MS/MS analysis. Then the effect of YOD1‐mediated motor deficits and oxidative damage were investigated using open field test, swimming test, pole test, immunofluorescence (IF) and cellular analyses. Results YOD1 was highly expressed in PD patients and 6‐OHDA‐induced PD model mice and mediated reactive oxygen species (ROS) production. YOD1 KO ameliorated motor impairments and oxidative stress in PD model mice. YOD1 directly bound PKM2 and reduces its ubiquitination level by removing the K63‐linked ubiquitin chain of PKM2, thereby increasing the tetramer level and reducing the dimer level of PKM2. It then inhibited dimerized PKM2 entry into the nucleus and regulated Nrf2‐mediated antioxidant responses, but YOD1 does not change the stability of PKM2 protein. Conclusions Our study identifies YOD1 as a oxidative‐sensitive regulator of PD progression, operating via the YOD1‐PKM2‐Nrf2 axis. Targeting YOD1 may offer a novel therapeutic strategy for PD. Key points YOD1 is highly elevated in different PD model mice and patients with PD. YOD1 is a key regulator in oxidative stress and PD pathology. YOD1‐deficient exhibit a protective effect on neuronal oxidative injury. YOD1 targets PKM2-Nrf2 axis in response to oxidative stress.