FOCUS on Parkinson’s Disease: Y Xu and coworkers identified deubiquitinating enzyme USP25 as a susceptible locus for PD as just reported in PNAS. They showed that USP25 exacerbated dopaminergic neuronal loss and motor deficits in mouse PD models induced with MPTP. Mechanistically USP25 sabotaged mitophagy machinery in neurons by interacting with the autophagy receptor optineuron (OPTN). This disrupted optineuron’s association with K63-linked polyubiquitin chains, leading to impaired mitophagy and the accumulation of damaged mitochondria. Both genetic ablation and pharmacological inhibition of USP25 with AZ1 restored mitophagy, and alleviated PD symptoms in mice.
Focus Biomolecules offers AZ1 for research applications.
