RNA editing of microtubule-associated protein tau circular RNAs promotes their translation and tau tangle formation

Justin Ralph Welden, Giorgi Margvelani, Karol Andrea Arizaca Maquera, Bhavani Gudlavalleti, Sandra C. Miranda Sardón, Alexandre Rosa Campos, Noemie Robil, Daniel C. Lee, Alvaro G. Hernandez, Wang Xia Wang, Jing Di, Pierre De La Grange, Peter T. Nelson, Stefan Stamm

Research output: Contribution to journalArticlepeer-review

10 Scopus citations

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.

Original languageEnglish
Pages (from-to)12979-12996
Number of pages18
JournalNucleic Acids Research
Volume50
Issue number22
DOIs
StatePublished - Dec 9 2022

Bibliographical note

Publisher Copyright:
© 2022 The Author(s). Published by Oxford University Press on behalf of Nucleic Acids Research.

ASJC Scopus subject areas

  • Genetics

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