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

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Glatz, DC; Rujescu, D; Tang, Y; Berendt, FJ; Hartmann, AM; Faltraco, F; Rosenberg, C; Hulette, C; Jellinger, K; Hampel, H; Riederer, P; Möller, H-J; Andreadis, A; Henkel, K; Stamm, S

Published Date

  • February 2006

Published In

Volume / Issue

  • 96 / 3

Start / End Page

  • 635 - 644

PubMed ID

  • 16371011

International Standard Serial Number (ISSN)

  • 0022-3042

Digital Object Identifier (DOI)

  • 10.1111/j.1471-4159.2005.03552.x

Language

  • eng

Conference Location

  • England