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

ABSTRACT: Imbalanced accumulation of microtubule-associated protein tau containing three or four repeat domains (3R or 4R tau species) 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 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. Further, CircTau6 overexpression partially recapitulated molecular signatures that were seen in human tauopathic brains, and its expression was directly regulated by tauopathy-associated MAPT mutations. These findings identify the circTau6/cTau4R as an important post-transcriptional mechanism modulating tauopathy, which may be therapeutically targeted.

ORGANISM(S): Mus musculus

PROVIDER: GSE329170 | GEO | 2026/05/05

REPOSITORIES: GEO

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