Influence of FTDP-17 mutants on circular tau RNAs

Area of Science:

• Genetics
• Molecular Biology
• Neuroscience

Background:

• Frontotemporal dementia (FTD) is linked to mutations in the microtubule-associated protein tau (MAPT) gene.
• Specific MAPT mutations, particularly between exons 7 and 13, may affect the formation of tau circular RNAs (circRNAs) via alternative backsplicing.
• Circular RNAs are emerging as key regulators in gene expression and disease.

Purpose of the Study:

• To investigate the impact of frontotemporal dementia-17 (FTDP-17) mutations on MAPT circRNA formation and translation.
• To determine the role of ADAR enzymes, specifically ADAR1-p150, in circTau RNA editing and translation.
• To explore the interaction of circTau proteins with cellular factors like eukaryotic initiation factor 4B (eIF4B).

Main Methods:

• Analysis of representative FTDP-17 MAPT mutants to assess circRNA formation (12➔7 and 12➔10).
• Investigated the effect of ADAR1-p150 on circTau RNA expression and translation.
• Studied the interaction between 12➔7 circTau protein and eIF4B, and the impact of specific mutations on this interaction.

Main Results:

• Five FTDP-17 mutations increased 12➔7 circRNA formation; three increased 12➔10 circRNA.
• ADAR1-p150 editing significantly influenced circTau RNA expression, decreasing 12➔7 but increasing 12➔10 circRNA.
• ADAR activity strongly promoted circTau RNA translation, and 12➔7 circTau protein interacted with eIF4B, an interaction reduced by certain mutations.

Conclusions:

• MAPT point mutations can alter circRNA expression levels, potentially through pre-mRNA structural changes.
• RNA editing, particularly by ADAR1-p150, plays a critical role in circTau RNA translation, often surpassing the effects of mutations.
• Circular RNAs and their editing status are important considerations for understanding FTDP-17 pathogenesis.