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

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• Tauopathies are characterized by the accumulation of 3R/4R tau protein aggregates.
• The precise mechanisms causing tau imbalance, potentially linked to MAPT mRNA alternative splicing, remain under-investigated.
• Understanding these mechanisms is crucial for developing effective tauopathy treatments.

Purpose of the Study:

• To identify novel mechanisms regulating tau protein imbalance in the brain.
• To investigate the role of circular RNAs in tauopathy pathogenesis.
• To explore the functional consequences of a newly identified circular RNA derived from the MAPT gene.

Main Methods:

• Identification of circTau6, a circular RNA from the MAPT gene, in human brain tissue.
• Demonstration of rolling translation of circTau6 into cTau4R proteins.
• In vivo studies using human MAPT knock-in mice (hMAPT mice) to assess the effects of cTau4R upregulation.
• Analysis of molecular signatures in hMAPT mice and correlation with tauopathy-associated MAPT mutations.

Main Results:

• CircTau6 was identified and found to be rolling-translated into novel 4R tau variants (cTau4R).
• cTau4R proteins were intrinsically hyperphosphorylated and promoted tau phosphorylation and aggregation.
• Upregulation of cTau4R in hMAPT mice led to 4R and phosphorylated tau deposition, neuronal/synaptic damage, neuroinflammation, and cognitive deficits.
• CircTau6 overexpression mimicked molecular features of human tauopathic brains and its expression was regulated by MAPT mutations.

Conclusions:

• CircTau6 and its translated cTau4R proteins represent a novel post-transcriptional mechanism modulating tauopathy.
• This finding provides new insights into the molecular basis of tauopathies.
• Targeting circTau6/cTau4R may offer a therapeutic strategy for tauopathies.