Abstract
Tau exon 10, which encodes the second microtubule-binding repeat, is regulated by alternative splicing. Its alternative splicing generates Tau isoforms with three- or four-microtubule-binding repeats, named 3R-tau and 4R-tau. Adult human brain expresses equal levels of 3R-tau and 4R-tau. Imbalance of 3R-tau and 4R-tau causes Tau aggregation and neurofibrillary degeneration. In the present study, we found that splicing factor SRp55 (serine/arginine-rich protein 55) promoted Tau exon 10 inclusion. Knockdown of SRp55 significantly promoted Tau exon 10 exclusion. The promotion of Tau exon 10 inclusion by SRp55 required the arginine/serine-rich region, which was responsible for the subnucleic speckle localization. Dyrk1A (dual specificity tyrosine-phosphorylated and regulated kinase 1A) interacted with SRp55 and mainly phosphorylated its proline-rich domain. Phosphorylation of SRp55 by Dyrk1A suppressed its ability to promote Tau exon 10 inclusion. Up-regulation of Dyrk1A as in Down syndrome could lead to neurofibrillary degeneration by shifting the alternative splicing of Tau exon 10 to an increase in the ratio of 3R-tau/4R-tau.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Alternative Splicing*
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Animals
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COS Cells
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Cell Nucleus / genetics
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Cell Nucleus / metabolism*
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Cell Nucleus / pathology
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Chlorocebus aethiops
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Down Syndrome / genetics
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Down Syndrome / metabolism
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Down Syndrome / pathology
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Dyrk Kinases
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HEK293 Cells
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HeLa Cells
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Hep G2 Cells
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Humans
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Introns*
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism*
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Phosphoproteins / genetics
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Phosphoproteins / metabolism*
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Phosphorylation / genetics
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Protein Isoforms / genetics
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Protein Isoforms / metabolism
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Protein Serine-Threonine Kinases / biosynthesis*
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Protein Serine-Threonine Kinases / genetics
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Protein-Tyrosine Kinases / biosynthesis*
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Protein-Tyrosine Kinases / genetics
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RNA-Binding Proteins / genetics
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RNA-Binding Proteins / metabolism*
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Rats
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Serine-Arginine Splicing Factors
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Up-Regulation / genetics
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tau Proteins / genetics
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tau Proteins / metabolism*
Substances
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MAPT protein, human
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Mapt protein, rat
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Nuclear Proteins
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Phosphoproteins
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Protein Isoforms
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RNA-Binding Proteins
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SRSF6 protein, human
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tau Proteins
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Serine-Arginine Splicing Factors
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Protein-Tyrosine Kinases
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Protein Serine-Threonine Kinases