RNA editing of microtubule-associated protein tau circular RNAs promotes their translation and tau tangle formation
Abstract
Aggregation of the microtubule-associated protein tau characterizes tauopathies, including Alzheimer's disease and frontotemporal lobar degeneration (FTLD-Tau). Gene expression regulation of tau is complex and incompletely understood. Here we report that the human tau gene (MAPT) generates two circular RNAs (circRNAs) through backsplicing of exon 12 to either exon 7 (12→7 circRNA) or exon 10 (12→10 circRNA). Both circRNAs lack stop codons. The 12→7 circRNA contains one start codon and is translated in a rolling circle, generating a protein consisting of multimers of the microtubule-binding repeats R1–R4. For the 12→10 circRNA, a start codon can be introduced by two FTLD-Tau mutations, generating a protein consisting of multimers of the microtubule-binding repeats R2–R4, suggesting that mutations causing FTLD may act in part through tau circRNAs. Adenosine to inosine RNA editing dramatically increases translation of circRNAs and, in the 12→10 circRNA, RNA editing generates a translational start codon by changing AUA to AUI. Circular tau proteins self-aggregate and promote aggregation of linear tau proteins. Our data indicate that adenosine to inosine RNA editing initiates translation of human circular tau RNAs, which may contribute to tauopathies.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Dec 09, 2022
- Source ID
- 10.1093/nar/gkac1129
Entities
People
- Alexandre Rosa Campos
- Alvaro G Hernandez
- Bhavani Gudlavalleti
- Daniel C Lee
- Giorgi Margvelani
- Jing Di
- Justin Ralph Welden
- Karol Andrea Arizaca Maquera
- Noémie Robil
- Peter T. Nelson
- Pierre De La Grange
- Sandra C Miranda Sardón
- Stefan Stamm
- Wang-xia Wang
Organizations
- National Institute on Aging
- Sanford Burnham Prebys Medical Discovery Institute
- United States Department of Defense
- University of Illinois Urbana–Champaign
- University of Kentucky