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

ABSTRACT: 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 AMPKα 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE289385 | GEO | 2025/02/17

REPOSITORIES: GEO

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Project description:During pregnancy, the Zika virus (ZIKV) can be vertically transmitted, causing Congenital Zika Syndrome (CZS) in fetuses. ZIKV infection in early gestational trimesters increases the chances to develop CZS. This syndrome involves several pathologies with a difficult diagnosis, which usually occurs in the postnatal stage. In this work, we aim to identify biological processes and molecular pathways related to CZS development and propose a series of putative protein and metabolite biomarkers for CZS prognosis in early pregnancy trimesters. Twenty-five serum samples of pregnant women were analyzed. For biological analysis, samples were separated into 3 biological groups composed of a control group of healthy pregnant women and two groups of ZIKV-infected pregnant women bearing non- microcephalic and microcephalic fetuses. Control and ZIKV-infected groups - without microcephalic fetuses - were subdivided into healthy and Cognitive Developmental Delay (CDD) newborns for biomarker analysis. We detected over 1,000 proteins and 500 metabolites by bottom-up proteomics and untargeted metabolomics, respectively. Statistical approaches - (t-Student, Limma, ANOVA, and DIABLO) - were applied to find CZS differentially abundant proteins (DAP) and metabolites (DAM). Enrichment analysis (i.e., biological processes and molecular pathways) of the DAP and the DAM allowed us to identify the ECM organization and proteoglycans, amino acid metabolism, and arachidonic acid metabolism as signatures in the CZS development. Five proteins and four metabolites were selected as CZS biomarkers candidates. The protein-based model indicated superior performance values for the Vitamin K-dependent protein S, Selenoprotein P, Inter-alpha- trypsin inhibitor heavy chain H2, Kallistatin, and Protein Z-dependent protease inhibitor proteins. Furthermore, the metabolite-based model was able to predict CZS with a probability of 90%. Serum multi-omics analysis led us to propose for further studies nine potential biomarkers for CZS early prognosis with high sensitivity and specificity.

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

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