Loss of age-accumulated crh-1 circRNAs ameliorate amyloid β-induced toxicity in a C. elegans model for Alzheimers disease

Abstract

Circular RNAs (circRNAs) are non-coding RNAs mostly derived from exons of protein-coding genes via a back-splicing process. The expression of hundreds of circRNAs accumulates during healthy aging and is associated with Alzheimers disease (AD), characterized by the accumulation of amyloid-beta (A{beta}) proteins. In C. elegans, many circRNAs were previously found to accumulate during aging, with loss of age-accumulated circRNAs derived from the CREB gene (circ-crh-1) to increase mean lifespan. Here, we used C. elegans to study the effects of age-accumulated circRNAs on the age-related onset of A{beta}-toxicity. We found that circ-crh-1 mutations delayed A{beta}-induced muscle paralysis and lifespan phenotypes in a transgenic C. elegans strain expressing a full-length human A{beta}-peptide (A{beta}1-42) selectively in muscle cells (GMC101). The delayed A{beta} phenotypic defects were associated with inhibiting the deposition of A{beta} aggregates, and thus, genetic removal of circ-crh-1 provides protection against A{beta}-induced toxicity. Consistent with a detrimental role for age-accumulated circRNAs in AD, circ-crh-1 expression level is elevated after induction of A{beta} during aging, whereas linear crh-1 mRNA expression remains unchanged. Finally, we show that a circ-crh-1 upregulated collagen gene, col-49, promotes A{beta}-induced paralysis. Taken together, our results show that the loss of an age-accumulated circRNA exerts a protective role on A{beta}-induced toxicity, demonstrating the utility of C. elegans for studying circRNAs in AD and its relationship to aging.