Alzheimer’s Disease-Associated CircHomer1 can Inhibit the Expression of Long APP and MAPT mRNA Isoforms in the Frontal Cortex Via Competing for Binding to HuD
Circular RNAs (circRNAs) are a novel category of non-coding RNAs derived from the back-splicing and covalent joining of exons or introns. Recent studies have suggested that circRNAs are preferentially generated from synaptic plasticity-related genes and are particularly enriched in the brain. Although some circRNAs have been found to sequester microRNAs and others to associate with RNA-binding proteins (RBPs), the mechanism of action of most circRNAs remains poorly understood. Moreover, little is known about the potential involvement of circRNAs in Alzheimer’s disease (AD). Using circRNA-specific quantification, we had previously found that circHomer1, a neuronal-enriched circRNA derived from Homer protein homolog 1 (HOMER1) capable of regulating cognitive function, is significantly downregulated postmortem brains of patients with AD and robustly associated with clinical dementia ratings and AD-associated neuropathology. Here we show that in vivo knockdown (KD) of circHomer1 in mouse frontal cortex results in a significant upregulation of long Amyloid precursor protein (APP) and microtubule-associated protein tau (MAPT) mRNA isoforms, of which accumulation of their respective encoded proteins are the pathological hallmark of AD. Furthermore, we show that circHomer1 is predicted to directly bind to both of these mRNA isoforms, potentially competing for binding with ELAV-like protein 4 (ELAVL4 or HuD), an RBP associated with AD and known to both bind to circHomer1 and associate with the long APP mRNAs, to promote their stability. Lastly, we demonstrate that circHomer1 is reduced in iPSC-derived neurons from subjects with AD and in the cortex of the 5xFAD model of AD. Ongoing experiments are aimed at further investigating the role of circHomer1 in APP and MAPT gene regulation and AD-associated pathogenesis and examining the effects of different drugs on brain circHomer1 expression. Taken together, our work introduces novel molecular networks with potential importance for AD.
Otero, Madison; Grigorios Papageorgiou; Sophie E. Eckel; Marissa R. Westenskow; Ibrahim El-Sharkawy; Niko Nykänen; Bruno A. Benitez; Carlos Cruchaga; and Nikolaos Mellios. "Alzheimer’s Disease-Associated CircHomer1 can Inhibit the Expression of Long APP and MAPT mRNA Isoforms in the Frontal Cortex Via Competing for Binding to HuD." (2023). https://digitalrepository.unm.edu/hsc-bbhrd/125
Poster presented at the Brain & Behavioral Health Research Day 2023