Glycogen synthase kinase-3 plays a crucial role in tau exon 10 splicing and intranuclear distribution of SC35. Implications for Alzheimer's disease.
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.
Hernández
Félix
F
Centro de Biología Molecular Severo Ochoa Consejo Superior de Investigaciones Científicas/CSIC/Universidad Autónoma, Fac. Ciencias. Universidad Autónoma de Madrid, Cantoblanco, 28049 Madrid, Spain.
Pérez
Mar
M
Lucas
José J
JJ
Mata
Ana M
AM
Bhat
Ratan
R
Avila
Jesús
J
D017398:Alternative Splicing; D000544:Alzheimer Disease / Q000378:metabolism*; D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D001120:Arginine / Q000737:chemistry; D002467:Cell Nucleus / Q000378:metabolism*; D002478:Cells, Cultured; D005091:Exons; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism / Q000502:physiology*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D051379:Mice; D008856:Microscopy, Fluorescence; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D009474:Neurons / Q000378:metabolism; D009687:Nuclear Proteins / Q000096:biosynthesis*; D010455:Peptides / Q000737:chemistry; D010766:Phosphorylation; D011233:Precipitin Tests; D020033:Protein Isoforms; D012326:RNA Splicing; D012333:RNA, Messenger / Q000378:metabolism; D012261:Ribonucleoproteins; D012694:Serine / Q000737:chemistry; D000068103:Serine-Arginine Splicing Factors; D013997:Time Factors; D016875:tau Proteins / Q000096:biosynthesis / Q000235:genetics*
D009687:Nuclear Proteins; D010455:Peptides; D020033:Protein Isoforms; D012333:RNA, Messenger; D012261:Ribonucleoproteins; C499372:SRSF2 protein, mouse; D016875:tau Proteins; C073288:SRSF2 protein, human; D000068103:Serine-Arginine Splicing Factors; D012694:Serine; D001120:Arginine; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3