2. Academic Validation
  3. DISC1 Protects Against Zika Virus Infection and Long-Term Neurological Damage Through AMPK-mTOR-Mediated Autophagy

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

  • Nat Commun. 2025 Nov 7;16(1):9841. doi: 10.1038/s41467-025-64809-w.
Shengze Zhang # 1 2,  Haolu Zha # 1 2,  Qiqi Chen # 1 2,  Nina Li 1 2,  Chengying Zheng 1 2,  Ting Xie 1 2,  Pengjie Ma 1 2,  Weijian Tian 1 2,  Shaohui Bai 1 2,  Chuming Luo 1 2,  Ning Wang 3,  Xuan Zou 4,  Shisong Fang 4,  Ying Jiang 5,  Jianhui Yuan 5,  Nan Wu 5,  Caijun Sun 1 2,  Yuelong Shu 1 2 6,  Huanle Luo 7 8
Affiliations

Affiliations

  • 1 School of Public Health (Shenzhen), Shenzhen Key Laboratory of Pathogenic Microbes and Biosafety, Shenzhen Campus of Sun Yat-sen University, Shenzhen, 518107, P.R. China.
  • 2 Key Laboratory of Tropical Disease Control (Sun Yat-sen University), Ministry of Education, Guangzhou, 510080, P.R. China.
  • 3 Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, China.
  • 4 Shenzhen Center for Disease Control and Prevention, Shenzhen, 518073, P.R. China.
  • 5 Shenzhen Nanshan Center for Disease Control and Prevention, Shenzhen, 518054, P.R. China.
  • 6 Key Laboratory of Pathogen Infection Prevention and Control (MOE), State Key Laboratory of Respiratory Health and Multimorbidity, National Institute of Pathogen Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 102629, P. R. China.
  • 7 School of Public Health (Shenzhen), Shenzhen Key Laboratory of Pathogenic Microbes and Biosafety, Shenzhen Campus of Sun Yat-sen University, Shenzhen, 518107, P.R. China. [email protected].
  • 8 Key Laboratory of Tropical Disease Control (Sun Yat-sen University), Ministry of Education, Guangzhou, 510080, P.R. China. [email protected].
  • # Contributed equally.
PMID: 41203603 DOI: 10.1038/s41467-025-64809-w
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.

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