DISC1 Protects Against Zika Virus Infection and Long-Term Neurological Damage Through AMPK-mTOR-Mediated Autophagy
Disrupted in Schizophrenia 1 (DISC1) is essential for neuronal development and has been implicated in various psychiatric disorders. However, its role in Zika virus (ZIKV) infection, particularly in congenital Zika syndrome (CZS) and ZIKV-induced long-term neurodevelopmental defects, remains unexplored. In this study, we demonstrate that DISC1 suppresses ZIKV infection in human placental and neuroglia cells, as well as in murine macrophages. DISC1 also limits ZIKV dissemination from peripheral tissues to key organs of mice, including the uterus, testis, and brain, thereby reducing fetal abortion rates and intrauterine growth restriction. Notably, DISC1 is associated with long-term ZIKV effects, including memory loss, reduced anxiety and depression, declines in sociability and social novelty. Mechanistically, DISC1 activates autophagy by enhancing AMPKa phosphorylation and reducing mTOR phosphorylation, protecting against ZIKV infection. Additionally, DISC1 interacts with LC3 to further activate autophagy, partially contributing to inhibit ZIKV infection. In conclusion, DISC1 plays a critical factor in controlling ZIKV infection and mitigating CZS and ZIKV-induced neurocognitive decline. Overall design: U251 cells were infected with ZIKV GZ01 (MOI of 1.0) post pcDNA or HA-DISC1 transfection for 24 hours.