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

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 4R tau variants containing the second microtubule-binding repeat, namely cTau4R. The cTau4R proteins were intrinsically hyperphosphorylated and promoted phosphorylation of naive tau proteins derived from linear MAPT mRNA. Upregulation of cTau4R led to deposition of 4R and phosphorylated tau forms in human MAPT knock-in mice (hMAPT mice), accompanied by neuronal and synaptic damages, neuroinflammation, and cognitive deficits.