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. 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.
Authors
- Huanle Luo (ORCID: https://orcid.org/0000-0002-0367-6888)
- Jianhui Yuan (ORCID: https://orcid.org/0000-0001-9200-3871)
- Caijun Sun (ORCID: https://orcid.org/0000-0002-2000-7053)
- Shengze Zhang
- Nina Li
- Pengjie Ma (ORCID: https://orcid.org/0000-0002-4766-1936)
- Ting Xie (ORCID: https://orcid.org/0000-0003-1159-5540)
- Qiqi Chen (ORCID: https://orcid.org/0009-0001-8920-2711)
- Shaohui Bai
- Chenlu Zheng (ORCID: https://orcid.org/0000-0001-6024-1541)
- Xuan Zou (ORCID: https://orcid.org/0000-0002-1145-5508)
- Chuming Luo
- Nan Wu (ORCID: https://orcid.org/0000-0002-9429-2889)
- Shisong Fang (ORCID: https://orcid.org/0000-0003-1684-5246)
- Ning Wang (ORCID: https://orcid.org/0000-0002-1391-9441)
- Ying Jiang (ORCID: https://orcid.org/0009-0002-0642-4106)
- Yuelong Shu (ORCID: https://orcid.org/0000-0001-9279-0916)
- Weijian Tian
- Haolu Zha
Institutions
- Sun Yat-sen University (CN)
- Shenzhen University (CN)
- Chinese Academy of Sciences (CN)
- Chinese Academy of Medical Sciences & Peking Union Medical College (CN)
- Shenzhen Center for Disease Control and Prevention (CN)
- Shenzhen University Health Science Center (CN)
- Shenzhen Institutes of Advanced Technology (CN)
- Shenzhen Nanshan Center for Chronic Disease Control (CN)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-11-07
- DOI
- https://doi.org/10.1038/s41467-025-64809-w
- Citations
- 1
- Primary Topic
- Phosphodiesterase function and regulation
- Type
- article
- Field-Weighted Citation Impact
- 0.81
Funders
- National Natural Science Foundation of China
- Sanming Project of Medicine in Shenzhen
- Science and Technology Planning Project of Guangdong Province