m6A-dependent circular RNA formation mediates tau-induced neurotoxicity

Abstract

ABSTRACTCircular RNAs (circRNAs), covalently closed RNA molecules that form due to back-splicing of RNA transcripts, have recently been implicated in Alzheimer’s disease and related tauopathies. circRNAs are regulated by N6-methyladenosine (m6A) RNA methylation, can serve as “sponges” for proteins and RNAs, and can be translated into protein via a cap-independent mechanism. Mechanisms underlying circRNA dysregulation in tauopathies and causal relationships between circRNA and neurodegeneration are currently unknown. In the current study, we aimed to determine whether pathogenic forms of tau drive circRNA dysregulation and whether such dysregulation causally mediates neurodegeneration. We identify circRNAs that are differentially expressed in the brain of aDrosophilamodel of tauopathy and in induced pluripotent stem cell (iPSC)-derived neurons carrying a tau mutation associated with autosomal dominant tauopathy. We leverageDrosophilato discover that depletion of circular forms ofmuscleblind(circMbl), a circRNA that is particularly abundant in brains of tau transgenicDrosophila, significantly suppresses tau neurotoxicity, suggesting that tau-inducedcircMblelevation is neurotoxic. We detect a general elevation of m6A RNA methylation and circRNA methylation in tau transgenicDrosophilaand find that tau-induced m6A methylation is a mechanistic driver ofcircMblformation. Interestingly, we find that circRNA and m6A RNA accumulate within nuclear envelope invaginations of tau transgenicDrosophilaand in iPSC-derived cerebral organoid models of tauopathy. Taken together, our studies add critical new insight into the mechanisms underlying circRNA dysregulation in tauopathy and identify m6A-modified circRNA as a causal factor contributing to neurodegeneration. These findings add to a growing literature implicating pathogenic forms of tau as drivers of altered RNA metabolism.