Alzheimer‐associated circular RNA circHOMER1 regulates synaptic gene expression and cognition
Year: 2020
Type: article
Study design: Observational Study
Abstract: Background Circular RNAs (circRNAs) are an unexplored and novel type of non‐coding RNA generated by backsplicing and covalent joining of exons and introns, which are rarely translated into protein. Recent studies have demonstrated that circRNAs are enriched in the brain and differentially altered during aging. However, the mechanism of action of most brain‐expressed circRNAs remains elusive and very little is known about their relevance in neurological disorders. Here, we conducted a circular‐transcriptome‐wide analysis of the differential expression of circRNA in AD cases and their correlation with clinical and neuropathological AD severity measures. Methods We generated paired‐end 151‐nt, paired‐end, rRNA‐depleted, and RNA sequencing data from frozen parietal cortex tissue from 83 AD patients and 13 controls. We aligned this data to the human reference genome (GRCh38) using STAR and called circRNAs using DCC software. circRNA differential expression (DE) analysis was performed using DESeq2 software. The superior temporal cortex RNA sequencing data from the Mount Sinai Brain Bank (195 individuals) was used as replication cohort. We investigated the association of human cortical circRNA expression with AD case–control status, Clinical dementia rating (CDR) and Braak score. Results A total of 3,146 well‐supported circRNAs common to both the discovery and the replication datasets were analyzed. Overall, 164 circRNAs were significantly associated with at least one AD trait in the meta‐analyses. Among them, three circRNAs, circHOMER1, circKCNN2 and circMAN2A1, were significantly associated with CDR score, Braak score and case‐control status. CircHOMER1, a neuronal‐enriched circRNA abundantly expressed in the brain explained 14.3% and 5.8% of the CDR variation in both cohorts. In vivo knockdown of circHomer1 in the mouse frontal cortex alters synaptic gene expression and disrupts cognitive flexibility. Moreover, circHomer1 can bind to an RNA‐binding protein that can increase its synaptic localization. Lastly, ongoing work is aimed at understanding how circHomer1 can affect synaptic gene expression and synaptic transmission. Conclusion Multiple circRNAs are differentially expressed in AD brain and are associated with clinical and neuropathological traits. At least one AD‐associated circRNA regulates synaptic gene expression and cognition. circRNAs may yield novel biomarkers or therapeutic targets for AD.
Source: Alzheimer s & Dementia
DOI: 10.1002/alz.042335
Language: English
Topic: Circular RNAs in diseases
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: bronze
OpenAlex ID: W3112193326