Alpha-synuclein expression in neuron modulates the Japanese encephalitis virus infection

Japanese encephalitis virus (JEV) stands as a prominent vector-borne zoonotic pathogen, displaying neurotropism and eliciting Parkinson's disease (PD)-like symptoms among most symptomatic survivors. A characteristic feature of PD is aggregation of mutated α-synuclein (α-syn) that damages the dopaminergic neurons. Considering this link between JEV-induced PD-like symptoms and α-syn pathogenesis, we explored the role of α-syn in JEV infectivity in neuronal cells. Our investigation revealed significant increase in endogenous α-syn expression in JEV-infected cells. Additionally, treatment with exogenous α-syn (Exoα-syn) led to a substantial reduction in JEV replication, suggesting its anti-JEV effect. Furthermore, Exoα-syn treatment led to the upregulation of superoxide dismutase 1 (SOD1) and reduction in reactive oxygen species (ROS). The results were validated by endogenous α-syn-silencing, that decreased SOD1 level and raised ROS level in neuronal cells. Similarly, the SOD1 inhibition via LCS-1 also intensified ROS and JEV infection. Overall, our results suggest that α-syn exerts an anti-JEV effect by regulating protein involved in oxidative stress inside neuronal cells. This study contributes valuable insights into the interplay between α-syn expression and JEV infectivity, shedding light on avenues to further investigate the potential role of α-syn in JEV pathogenesis.