Complex regulation of tau exon 10, whose missplicing causes frontotemporal dementia

Qing Sheng Gao, John Memmott, Robert Lafyatis, Stefan Stamm, Gavin Screaton, Athena Andreadis

Research output: Contribution to journalArticlepeer-review

77 Scopus citations

Abstract

Tau is a microtubule-associated protein whose transcript undergoes complex regulated splicing in the mammalian nervous system. Exon 10 of the gene is an alternatively spliced cassette that is adult-specific and that codes for a microtubule binding domain. Recently, mutations that affect splicing of exon 10 have been shown to cause inherited frontotemporal dementia (FTDP). In this study, we establish the endogenous expression patterns of exon 10 in human tissue; by reconstituting naturally occurring FTDP mutants in the homologous context of exon 10, we show that the cis determinants of exon 10 splicing regulation include an exonic silencer within the exon, its 5' splice site, and the relative affinities of its flanking exons to it. By cotransfections in vivo, we demonstrate that several splicing regulators affect the ratio of tau isoforms by inhibiting exon 10 inclusion.

Original languageEnglish
Pages (from-to)490-500
Number of pages11
JournalJournal of Neurochemistry
Volume74
Issue number2
DOIs
StatePublished - 2000

Keywords

  • Expression pattern of regulated isoforms
  • Frontotemporal dementia
  • Microtubule binding domain
  • Microtubule-associated protein tau
  • Regulation of alternative splicing

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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