USP9X suppression attenuates NLRP3 inflammasome activation and ameliorates neuroinflammatory phenotypes with motor function recovery in murine models.

Parkinson's disease (PD) is characterized by the progressive degeneration of dopaminergic neurons in the substantia nigra and striatum, which accompanied by the activation of NLRP3 inflammasome, autophagic dysfunction and motor disorders. USP9X, as a highly conserved ubiquitin-specific protease, which abnormal expression is closely correlated with various neurodegenerative diseases and neurodevelopmental disorders. However, whether USP9X can regulate the activation of NLRP3 inflammasome in Parkinson's disease (PD) has not been elucidated yet. In this study, LPS was intraperitoneally injected into wild-type mice to simulate neuroinflammation of Parkinson's disease and USP9X-shRNA was stereotactic injected into bilateral lateral ventricles (LV) of the mice brain to inhibit the expression of USP9X. The results showed that inhibition of USP9X expression could siginificantly improve the motor dysfunction, activation of NLRP3 inflammasome, degeneration of dopaminergic neurons and activation of microglia induced by LPS. Additionally, the parkin+/- mice exhibited great activation of the NLRP3 inflammasome, loss of dopaminergic neurons and motor dysfunction at an early age. However, downregulation of USP9X expression in parkin+/- mice also significantly improved the activation of the NLRP3 inflammasome, damage to dopaminergic neurons, autophagic dysfunction and motor dysfunction. Therefore, USP9X can be utilized as an effective potential target for inhibiting NLRP3 inflammasomes activation and activating the autophagic function, which expected to be a potential therapeutic strategy for Parkinson's disease.