Overexpression of Dyrk1A contributes to neurofibrillary degeneration in Down syndrome.
Adults with Down syndrome (DS) develop Alzheimer neurofibrillary degeneration in the brain, but the underlying molecular mechanism is unknown. Here, we report that the presence of an extra copy of the dual-specificity tyrosine-phosphorylated and regulated kinase 1A (Dyrk1A) gene due to trisomy 21 resulted in overexpression of Dyrk1A and elevated kinase activity in DS brain. Dyrk1A phosphorylated tau at several sites, and these sites were hyperphosphorylated in adult DS brains. Phosphorylation of tau by Dyrk1A primed its further phosphorylation by glycogen synthase kinase-3beta (GSK-3beta). Dyrk1A-induced tau phosphorylation inhibited tau's biological activity and promoted its self-aggregation. In Ts65Dn mouse brain, an extra copy of the Dyrk1A gene caused increased expression and activity of Dyrk1A and resulted in increased tau phosphorylation. These findings strongly suggest a novel mechanism by which the overexpression of Dyrk1A in DS brain causes neurofibrillary degeneration via hyperphosphorylating tau.
Department of Neurochemistry, New York State Institute for Basic Research in Developmental Disabilities, 1050 Forest Hill Rd., Staten Island, New York 10314, USA.
Fei
F
Liu
Zhihou
Z
Liang
Jerzy
J
Wegiel
Yu-Wen
YW
Hwang
Khalid
K
Iqbal
Inge
I
Grundke-Iqbal
Narayan
N
Ramakrishna
Cheng-Xin
CX
Gong
D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D004314:Down Syndrome / Q000473:pathology* / Q000503:physiopathology; D005260:Female; D018507:Gene Expression Regulation, Developmental; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D009410:Nerve Degeneration / Q000473:pathology*; D016874:Neurofibrillary Tangles / Q000473:pathology*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis* / Q000502:physiology; D011505:Protein-Tyrosine Kinases / Q000096:biosynthesis* / Q000502:physiology; D016875:tau Proteins / Q000378:metabolism; D000097603:Dyrk Kinases
D038362:Glycogen Synthase Kinase 3; D000071679:Glycogen Synthase Kinase 3 beta; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D016875:tau Proteins; D000097603:Dyrk Kinases; C054369:MAPT protein, human; C000605506:GSK3B protein, human; C000605507:Gsk3b protein, mouse