title: Regulation of the alternative splicing of tau exon 10 by SC35 and Dyrk1A.
abstract: Abnormal alternative splicing of tau exon 10 results in imbalance of 3R-tau and 4R-tau expression, which is sufficient to cause neurofibrillary degeneration. Splicing factor SC35, a member of the superfamily of the serine/arginine-rich (SR) proteins, promotes tau exon 10 inclusion. The molecular mechanism by which SC35 participates in tau exon 10 splicing remains elusive. In the present study, we found that tau pre-mRNA was coprecipitated by SC35 tagged with HA. Mutation of the SC35-like exonic splicing enhancer located at exon 10 of tau affected both the binding of SC35 to tau pre-mRNA and promotion of tau exon 10 inclusion, suggesting that SC35 acts on the SC35-like exonic splicing enhancer to promote tau exon 10 inclusion. Dyrk1A (dual-specificity tyrosine-phosphorylated and regulated kinase 1A) phosphorylated SC35 in vitro and interacted with it in cultured cells. Overexpression of Dyrk1A suppressed SC35's ability to promote tau exon 10 inclusion. Downregulation of Dyrk1A promoted 4R-tau expression. Therefore, upregulation of Dyrk1A in Down syndrome brain or Alzheimer's brain may cause dysregulation of tau exon 10 splicing through SC35, and probably together with other splicing factors, leading to the imbalance in 3R-tau and 4R-tau expression, which may initiate or accelerate tau pathology and cause neurofibrillary degeneration in the diseases.
authors.affiliation: Jiangsu Key Laboratory of Neuroregeneration, Department of Biochemistry, Medical School, Nantong University, Nantong, Jiangsu, PR China.
authors.forename: Wei
authors.initials: W
authors.lastname: Qian
authors.forename: Hongwei
authors.initials: H
authors.lastname: Liang
authors.forename: Jianhua
authors.initials: J
authors.lastname: Shi
authors.forename: Nana
authors.initials: N
authors.lastname: Jin
authors.forename: Inge
authors.initials: I
authors.lastname: Grundke-Iqbal
authors.forename: Khalid
authors.initials: K
authors.lastname: Iqbal
authors.forename: Cheng-Xin
authors.initials: CX
authors.lastname: Gong
authors.forename: Fei
authors.initials: F
authors.lastname: Liu
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D005091:Exons; D006801:Humans; D009687:Nuclear Proteins / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D012322:RNA Precursors / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D012261:Ribonucleoproteins / Q000378:metabolism*; D000068103:Serine-Arginine Splicing Factors; D016875:tau Proteins / Q000235:genetics* / Q000378:metabolism; D000097603:Dyrk Kinases
chemical_list: D009687:Nuclear Proteins; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D012322:RNA Precursors; D012333:RNA, Messenger; D012261:Ribonucleoproteins; D000068103:Serine-Arginine Splicing Factors; D016875:tau Proteins; D000097603:Dyrk Kinases; C499372:SRSF2 protein, mouse