DISC1 Protects Against Zika Virus Infection and Long-Term Neurological Damage Through AMPK-mTOR-Mediated Autophagy

Shengze Zhang, Haolu Zha, Qiqi Chen, Nina Li, Chengying Zheng, Ting Xie, Pengjie Ma, Weijian Tian, Shaohui Bai, Chuming Luo, Ning Wang, Xuan Zou, Shisong Fang, Ying Jiang, Jianhui Yuan, Nan Wu, Caijun Sun, Yuelong Shu and Huanle Luo ()
Additional contact information
Shengze Zhang: Shenzhen Campus of Sun Yat-sen University
Haolu Zha: Shenzhen Campus of Sun Yat-sen University
Qiqi Chen: Shenzhen Campus of Sun Yat-sen University
Nina Li: Shenzhen Campus of Sun Yat-sen University
Chengying Zheng: Shenzhen Campus of Sun Yat-sen University
Ting Xie: Shenzhen Campus of Sun Yat-sen University
Pengjie Ma: Shenzhen Campus of Sun Yat-sen University
Weijian Tian: Shenzhen Campus of Sun Yat-sen University
Shaohui Bai: Shenzhen Campus of Sun Yat-sen University
Chuming Luo: Shenzhen Campus of Sun Yat-sen University
Ning Wang: Chinese Academy of Sciences
Xuan Zou: Shenzhen Center for Disease Control and Prevention
Shisong Fang: Shenzhen Center for Disease Control and Prevention
Ying Jiang: Shenzhen Nanshan Center for Disease Control and Prevention
Jianhui Yuan: Shenzhen Nanshan Center for Disease Control and Prevention
Nan Wu: Shenzhen Nanshan Center for Disease Control and Prevention
Caijun Sun: Shenzhen Campus of Sun Yat-sen University
Yuelong Shu: Shenzhen Campus of Sun Yat-sen University
Huanle Luo: Shenzhen Campus of Sun Yat-sen University

Nature Communications, 2025, vol. 16, issue 1, 1-20

Abstract: Abstract Disrupted in Schizophrenia 1 (DISC1) is essential for neuronal development and has been implicated in various psychiatric disorders. Our transcriptomic and proteomic analyses identified Zika virus (ZIKV) infection enhanced DISC1 expression, however, its functional role in ZIKV infection and caused congenital Zika syndrome (CZS) and ZIKV-induced long-term neurodevelopmental defects remain unexplored. In this study, we demonstrate that DISC1 attenuates ZIKV infection in human placental and neuroglia cells, as well as in murine macrophages and primary cortical cells. DISC1 also decreases 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 brain damage and long-term ZIKV effects, including memory loss, reduced anxiety and depression, declines in sociability and social novelty. Mechanistically, DISC1 activates autophagy by enhancing AMPKα phosphorylation and reducing mTOR phosphorylation, protecting against ZIKV infection. Additionally, DISC1 interacts with LC3 to further activate autophagy, partially contributing to reduce ZIKV infection. In conclusion, DISC1 plays a critical factor in controlling ZIKV infection and mitigating CZS and ZIKV-induced neurocognitive decline.

Date: 2025
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DOI: 10.1038/s41467-025-64809-w

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