Increased dosage of Dyrk1A alters alternative splicing factor (ASF)-regulated alternative splicing of tau in Down syndrome.
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.
Shi
Jianhua
J
Jiangsu Key Laboratory of Neuroregeneration, Nantong University, Nantong, Jiangsu 226001, P. R. China.
Zhang
Tianyi
T
Zhou
Chunlei
C
Chohan
Muhammad Omar
MO
Gu
Xiaosong
X
Wegiel
Jerzy
J
Zhou
Jianhua
J
Hwang
Yu-Wen
YW
Iqbal
Khalid
K
Grundke-Iqbal
Inge
I
Gong
Cheng-Xin
CX
Liu
Fei
F
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
D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D012694:Serine; D016875:tau Proteins; D000097603:Dyrk Kinases; C054369:MAPT protein, human