The human MAPT locus generates circular RNAs

Justin R. Welden, Jacob van Doorn, Peter T. Nelson, Stefan Stamm

Research output: Contribution to journalArticlepeer-review

22 Scopus citations

Abstract

The microtubule-associated protein Tau, generated by the MAPT gene is involved in dozens of neurodegenerative conditions (“tauopathies”), including Alzheimer's disease (AD) and frontotemporal lobar degeneration/frontotemporal dementia (FTLD/FTD). The pre-mRNA of MAPT is well studied and its aberrant pre-mRNA splicing is associated with frontotemporal dementia. Using a PCR screen of RNA from human brain tissues, we found that the MAPT locus generates circular RNAs through a backsplicing mechanism from exon 12 to either exon 10 or 7. MAPT circular RNAs are localized in the cytosol and contain open reading frames encoding Tau protein fragments. The MAPT exon 10 is alternatively spliced and proteins involved in its regulation, such as CLK2, SRSF7/9G8, PP1 (protein phosphatase 1) and NIPP1 (nuclear inhibitor of PP1) reduce the abundance of the circular MAPT exon 12 → 10 backsplice RNA after being transfected into cultured HEK293 cells. In summary, we report the identification of new bona fide human brain RNAs produced from the MAPT locus. These may be a component of normal human brain Tau regulation and, since the circular RNAs could generate high molecular weight proteins with multiple microtubule binding sites, they could contribute to taupathies.

Original languageEnglish
Pages (from-to)2753-2760
Number of pages8
JournalBiochimica et Biophysica Acta - Molecular Basis of Disease
Volume1864
Issue number9
DOIs
StatePublished - Sep 2018

Bibliographical note

Publisher Copyright:
© 2018

Keywords

  • Alternative pre-mRNA splicing
  • Alzheimer's disease
  • Circular RNAs
  • Gene expression
  • Tau

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology

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