Influence of FTDP-17 mutants on circular Tau RNAs

Area of Science:

• Molecular Biology
• Genetics
• Neuroscience

Background:

• Frontotemporal dementia (FTDP-17) is linked to mutations in the microtubule-associated protein tau gene (MAPT).
• Many MAPT mutations are located in regions affecting circular RNA (circRNA) formation via backsplicing.
• The role of circRNAs in FTDP-17 pathogenesis is not well understood.

Approach:

• Analyzed MAPT mutations' effects on circRNA formation (12➔7 and 12➔10 circRNAs).
• Investigated the influence of adenosine to inosine editing by ADAR1-p150 on circTau RNA translation.
• Examined the interaction between circTau proteins and eukaryotic initiation factor 4B (eIF4B).

Key Points:

• Specific FTDP-17 mutations alter the expression levels of 12➔7 and 12➔10 circRNAs.
• ADAR1-p150 editing significantly impacts circTau RNA translation and expression, with differential effects on circRNA isoforms.
• circTau proteins interact with eIF4B, and this interaction is disrupted by certain FTDP-17 mutations.

Conclusions:

• MAPT mutations influence circRNA expression and translation, independent of protein levels.
• RNA editing plays a crucial role in circTau protein production.
• circRNAs and their editing represent potential therapeutic targets for FTDP-17.