Glycogen synthase kinase-3 plays a crucial role in tau exon 10 splicing and intranuclear distribution of SC35. Implications for Alzheimer's disease

J Biol Chem. 2004 Jan 30;279(5):3801-6. doi: 10.1074/jbc.M311512200. Epub 2003 Nov 5.


Tauopathies, including Alzheimer's disease, are neurodegenerative disorders in which tau protein accumulates as a consequence of alterations in its metabolism. At least three different types of alterations have been described; in some cases, an aberrant mRNA splicing of tau exon 10 occurs; in other cases, the disorder is a consequence of missense mutations and, in most cases, aberrant tau hyperphosphorylation takes place. Glycogen synthase kinase-3 (GSK-3) has emerged as a key kinase that is able to interact with several proteins involved in the etiology of Alzheimer's disease and other tauopathies. Here, we have evaluated whether GSK-3 is also able to modulate tau-mRNA splicing. Our data demonstrate that GSK-3 inhibition in cultured neurons affects tau splicing resulting in an increase in tau mRNA containing exon 10. Pre-mRNA splicing is catalyzed by a multimolecular complex including members of the serine/arginine-rich (SR) family of splicing factors. Immunofluorescence studies showed that after GSK-3 inhibition, SC35, a member of the SR family, is redistributed and enriched in nuclear speckles and colocalizes with the kinase. Furthermore, immunoprecipitated SC35 is phosphorylated by recombinant GSK-3beta. Phosphorylation of a peptide from the SR domain by GSK-3 revealed that the peptide needs to be prephosphorylated, suggesting the involvement of a priming kinase. Our results demonstrate that GSK-3 plays a crucial role in tau exon 10 splicing, raising the possibility that GSK3 could contribute to tauopathies via aberrant tau splicing.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alternative Splicing
  • Alzheimer Disease / metabolism*
  • Amino Acid Motifs
  • Amino Acid Sequence
  • Animals
  • Arginine / chemistry
  • Cell Nucleus / metabolism*
  • Cells, Cultured
  • Exons
  • Glycogen Synthase Kinase 3 / metabolism
  • Glycogen Synthase Kinase 3 / physiology*
  • Glycogen Synthase Kinase 3 beta
  • Humans
  • Mice
  • Microscopy, Fluorescence
  • Molecular Sequence Data
  • Mutation, Missense
  • Neurons / metabolism
  • Nuclear Proteins / biosynthesis*
  • Peptides / chemistry
  • Phosphorylation
  • Precipitin Tests
  • Protein Isoforms
  • RNA Splicing*
  • RNA, Messenger / metabolism
  • Ribonucleoproteins*
  • Serine / chemistry
  • Serine-Arginine Splicing Factors
  • Time Factors
  • tau Proteins / biosynthesis
  • tau Proteins / genetics*


  • Nuclear Proteins
  • Peptides
  • Protein Isoforms
  • RNA, Messenger
  • Ribonucleoproteins
  • SRSF2 protein, mouse
  • tau Proteins
  • SRSF2 protein, human
  • Serine-Arginine Splicing Factors
  • Serine
  • Arginine
  • GSK3B protein, human
  • Glycogen Synthase Kinase 3 beta
  • Gsk3b protein, mouse
  • Glycogen Synthase Kinase 3