Project description:Our lab and others have shown that chronic alcohol use leads to gene and miRNA expression changes across the mesocorticolimbic (MCL) system. Circular-RNA (circRNA) are noncoding RNA that form closed-looped structures and are reported to alter gene expression through miRNA sequestration, thus providing a potentially novel neurobiological mechanism for the development of alcohol dependence (AD). Genome-wide expression of circRNA was assessed in nucleus accumbens (NAc) from 32 AD matched cases/controls. Significant circRNA (unadj. p≤0.05) were identified via regression and clustered in circRNA networks via WGCNA. CircRNA interactions with previously generated mRNA and miRNA were detected via correlation and bioinformatic analyses. MatrixeQTL was used to identify eQTLs affecting circRNA expression. Genomic enrichment was used to detect overlap between eQTLs and recent GWAS of substance abuse. Significant circRNAs (N=542) clustered in 9 significant AD modules (FWER p≤0.05), within which we identified 137 circRNA hubs. We detected 23 significant circRNA:miRNA:mRNA interactions (FDR≤0.10). Among these, circRNA-406742 and miR-1200 significantly interact with the highest number of mRNA, including genes associated with neuronal functioning and alcohol addiction (HRAS, PRKCB, HOMER1, and PCLO). Finally, we identified 96 significant circRNA eQTLs (unadj. p≤0.002), showing significant enrichment within recent alcohol use disorder (AUD) and smoking GWAS. To our knowledge, this is the first study to examine the role of circRNA in the neuropathology of AD. We show that circRNA impact mRNA expression by interacting with miRNA in the NAc of AD subjects. We further identify genetic variants affecting circRNA expression impacting potential miRNA and mRNA interactions. More importantly, we provide indirect evidence for the clinical importance of circRNA in the development of AUD by detecting a significant enrichment of our circRNA eQTLs among GWAS of substance abuse.

Project description:Background Circular RNAs (circRNAs) are highly stable regulatory molecules, often accumulated in the mammalian brain and thought to serve as “memory molecules” that govern the long process of aging. Mounting evidence demonstrated circRNA dysregulation in postmortem cortical regions of Alzheimer’s disease (AD) patients. However, whether and how circRNA dysregulation underlies AD progression remains unexplored. Methods Poly(A)-tailing/RNase R digestion was coupled with our recently published computational algorithm CARP to identify genome-wide dysregulation of circRNAs and their downstream pathways in the 5xFAD mouse cerebral cortex between 5- and 7-month of age, a critical window that marks the transition from reversible to irreversible pathogenic progression. Irreversibly dysregulated circRNAs and pathways in 5xFAD cortex were systematically compared with a large human AD cohort study. A top ranked circRNA conserved and commonly affected in AD patients and 5xFAD mice was depleted in cultured cells to confirm its causal roles in AD-relevant molecular and cellular changes. Results We discovered genome-wide circRNA alterations specifically in the 5xFAD cortex associated with AD progression and found numerous circRNAs also consistently affected in AD patient postmortem cortical areas. Among such circRNAs, circGigyf2 showed the highest net reduction starting from 7-month of age, which is highly conserved and negatively correlated with human AD severity. Mechanistically, we found multiple AD-affected splicing factors that are essential for circGigyf2 biogenesis. Functionally, we identified and experimentally validated the conserved roles of circGigyf2 in sponging AD-relevant miRNAs and AD-associated RNA binding proteins (RBPs) including the cleavage and polyadenylation factor 6 (CPSF6). CircGigyf2 downregulation in AD exert silencing activities of its sponged miRNAs and aberrantly enhanced the polyadenylation efficiency of many CPSF6 targets. These post-transcriptionally tuned mRNAs by circGigyf2 were enriched in apoptotic pathways. Furthermore, circGigyf2 depletion in a mouse immortalized neuronal cell line dysregulated circGigyf2-miRNA and circGigyf2-CPSF6 axes and potentiated neuronal responses to apoptotic insults, which strongly support the causative role of circGigyf2 deficiency in AD disease progression. Conclusions Together, our results unveiled pathological alterations of the brain circRNA landscape associated with irreversible disease stage in an AD mouse model and identified novel molecular mechanisms underlying dysregulation of conserved circRNA pathways that contribute to AD pathogenesis.

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Dataset Information

Alzheimer’s Disease-Associated circPDE4B Triggers Translation Stress Pathways

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Publications

circPDE4B downregulation triggers GEMIN5‑dependent translational stress response and autophagy to reduce MAPT pathology.

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