title: Increased dosage of Dyrk1A alters alternative splicing factor (ASF)-regulated alternative splicing of tau in Down syndrome.
abstract: Two groups of tau, 3R- and 4R-tau, are generated by alternative splicing of tau exon 10. Normal adult human brain expresses equal levels of them. Disruption of the physiological balance is a common feature of several tauopathies. Very early in their life, individuals with Down syndrome (DS) develop Alzheimer-type tau pathology, the molecular basis for which is not fully understood. Here, we demonstrate that Dyrk1A, a kinase encoded by a gene in the DS critical region, phosphorylates alternative splicing factor (ASF) at Ser-227, Ser-234, and Ser-238, driving it into nuclear speckles and preventing it from facilitating tau exon 10 inclusion. The increased dosage of Dyrk1A in DS brain due to trisomy of chromosome 21 correlates to an increase in 3R-tau level, which on abnormal hyperphosphorylation and aggregation of tau results in neurofibrillary degeneration. Imbalance of 3R- and 4R-tau in DS brain by Dyrk1A-induced dysregulation of alternative splicing factor-mediated alternative splicing of tau exon 10 represents a novel mechanism of neurofibrillary degeneration and may help explain early onset tauopathy in individuals with DS.
authors.affiliation: Jiangsu Key Laboratory of Neuroregeneration, Nantong University, Nantong, Jiangsu 226001, P. R. China.
authors.forename: Jianhua
authors.initials: J
authors.lastname: Shi
authors.forename: Tianyi
authors.initials: T
authors.lastname: Zhang
authors.forename: Chunlei
authors.initials: C
authors.lastname: Zhou
authors.forename: Muhammad Omar
authors.initials: MO
authors.lastname: Chohan
authors.forename: Xiaosong
authors.initials: X
authors.lastname: Gu
authors.forename: Jerzy
authors.initials: J
authors.lastname: Wegiel
authors.forename: Jianhua
authors.initials: J
authors.lastname: Zhou
authors.forename: Yu-Wen
authors.initials: YW
authors.lastname: Hwang
authors.forename: Khalid
authors.initials: K
authors.lastname: Iqbal
authors.forename: Inge
authors.initials: I
authors.lastname: Grundke-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; D001921:Brain / Q000196:embryology / Q000378:metabolism; D019556:COS Cells; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D004314:Down Syndrome / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D008954:Models, Biological; D019636:Neurodegenerative Diseases / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D051381:Rats; D012694:Serine / Q000737:chemistry; D016875:tau Proteins / Q000737:chemistry*; D000097603:Dyrk Kinases
chemical_list: D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D012694:Serine; D016875:tau Proteins; D000097603:Dyrk Kinases; C054369:MAPT protein, human