MAPT-derived circTau6 induces tau pathogenesis and neurodegeneration by encoding Tau variants

Imbalanced accumulation of microtubule-associated protein tau containing three or four repeat domains (3 R or 4 R tau) is a core feature of tauopathies, which may result from alternative splicing of the MAPT mRNA. However, specific mechanisms yielding the imbalance were underinvestigated. Here, we identify a circular RNA (circTau6) derived from the MAPT gene in the human brain. CircTau6 was rolling-translated into novel 4 R tau variants, cTau4R. The cTau4R proteins were intrinsically hyperphosphorylated and promoted phosphorylation and aggregation of naive tau proteins derived from linear MAPT mRNA. Upregulation of cTau4R led to deposition of 4 R and phosphorylated tau forms in human MAPT knock-in mice (hMAPT mice), accompanied by neuronal and synaptic damage, neuroinflammation, and cognitive deficits. Further, CircTau6 overexpression partially recapitulated molecular signatures observed in human tauopathic brains, and its expression was directly regulated by tauopathy-associated MAPT mutations. These findings identify circTau6/cTau4R as a post-transcriptional mechanism that modulates tauopathy.