JWA antagonizes paraquat-induced neurotoxicity via activation of Nrf2.

Paraquat (PQ), a widely used environmental toxin in agriculture, contributes to the onset and progression of Parkinson's disease (PD) by damaging neurons. The JWA gene, also known as ARL6IP5, exerts a protective effect on degenerating dopamine (DA) neurons. However, the roles of JWA in PQ-induced neuronal damage are still unknown. In our study, two neuronal cell lines (HT-22 and SH-SY5Y) and neuron-specific JWA knockout (JWA-nKO) and age-matched wild-type (JWA-nWT) mice were subjected to PQ treatment. The results indicate that PQ administration triggers the upregulation of JWA. Elevated expression of JWA rescues the accumulation of reactive oxygen species (ROS) while increasing glutathione (GSH) and glutathione peroxidase (GPx) levels under PQ exposure. Further investigations revealed that the protective effect of JWA mostly involves regulation of the MEK/PI3K-Nrf2 axis. Our results suggest that JWA may be a novel target for the prevention and treatment of PQ-induced PD.