Tau is a microtubule-associated protein whose transcript undergoes regulated splicing in the mammalian nervous system. Exon 10 of the gene is an alternatively spliced cassette that is adult-specific and encodes a microtubule-binding domain. Mutations increasing the inclusion of exon 10 result in the production of tau protein which predominantly contains four microtubule-binding repeats and were shown to cause frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). Here we show that exon 10 usage is regulated by CDC2-like kinases CLK1, 2, 3, and 4 that phosphorylate serine-arginine-rich proteins, which in turn regulate pre-mRNA splicing. Cotransfection experiments suggest that CLKs achieve this effect by releasing specific proteins from nuclear storage sites. Our results show that changing pre-mRNA-processing pathways through phosphorylation could be a new therapeutic concept for tauopathies.
|Number of pages||11|
|Journal||Molecular and Cellular Neuroscience|
|State||Published - 2001|
Bibliographical noteFunding Information:
This work was supported by the Max Planck Society (S.S., E.M.), the DFG (Sta399/3-1) and the Johannes and Frieda Marohn Stiftung (Sta/00) (both to S.S.), NIH Grant Ro1-AG18486 to A.A. and the UK Medical Research Council.
ASJC Scopus subject areas
- Molecular Biology
- Cellular and Molecular Neuroscience
- Cell Biology