m6A-dependent circular RNA formation mediates tau-induced neurotoxicity.

Circular 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 N-methyladenosine (mA) 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 a model of tauopathy and in induced pluripotent stem cell (iPSC)-derived neurons carrying a tau mutation associated with autosomal dominant tauopathy. We leverage to discover that depletion of circular forms of (, a circRNA that is particularly abundant in brains of tau transgenic , significantly suppresses tau neurotoxicity, suggesting that tau-induced elevation is neurotoxic. We detect a general elevation of mA RNA methylation and circRNA methylation in tau transgenic and find that tau-induced mA methylation is a mechanistic driver of formation. Interestingly, we find that circRNA and mA RNA accumulate within nuclear envelope invaginations of tau transgenic and 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 mA-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.