The alternative splicing of tau exon 10 and its regulatory proteins CLK2 and TRA2-BETA1 changes in sporadic Alzheimer's disease

Daniela C. Glatz, Dan Rujescu, Yesheng Tang, Frank J. Berendt, Annette M. Hartmann, Frank Faltraco, Carlyn Rosenberg, Christine Hulette, Kurt Jellinger, Harald Hampel, Peter Riederer, Hans J. Möller, Athena Andreadis, Kerstin Henkel, Stefan Stamm

Research output: Contribution to journalArticlepeer-review

118 Scopus citations

Abstract

Pathological inclusions containing fibrillar aggregates of hyperphosphorylated tau protein are a characteristic feature in tauopathies, which include Alzheimer's disease (AD). Tau is a microtubule-associated protein whose transcript undergoes alternative splicing in the brain. Exon 10 encodes one of four microtubule-binding repeats. Exon 10 inclusion gives rise to tau protein isoforms containing four microtubule-binding repeats (4R) whereas exclusion leads to isoforms containing only three repeats (3R). The ratio between 3R and 4R isoforms is tightly controlled via alternative splicing in the human adult nervous system and distortion of this balance results in neurodegeneration. Previous studies showed that several splicing regulators, among them hTRA2-beta1 and CLK2, regulate exon 10 alternative splicing. Like most splicing factors, htra2-beta and clk2 pre-mRNAs are regulated by alternative splicing. Here, we investigated whether human postmortem brain tissue of AD patients reveal differences in alternative splicing patterns of the tau, htra2-beta, presenilin 2 and clk2 genes when compared with age-matched controls. We found that the splicing patterns of all four genes are altered in affected brain areas of sporadic AD patients. In these affected areas, the amount of mRNAs of tau isoforms including exon 10, the htra2-beta1 isoform and an inactive form of clk2 are significantly increased. These findings suggest that a misregulation of alternative splicing seems to contribute to sporadic AD.

Original languageEnglish
Pages (from-to)635-644
Number of pages10
JournalJournal of Neurochemistry
Volume96
Issue number3
DOIs
StatePublished - Feb 2006

Keywords

  • Alternative splicing
  • Alzheimer's disease
  • CDC-like kinase
  • Serine-arginine proteins
  • Tau

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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