The role of overexpressed DYRK1A protein in the early onset of neurofibrillary degeneration in Down syndrome.
The gene encoding the minibrain kinase/dual-specificity tyrosine phosphorylated and regulated kinase 1A (DYRK1A) is located in the Down syndrome (DS) critical region of chromosome 21. The third copy of DYRK1A is believed to contribute to abnormal brain development in patients with DS. In vitro studies showing that DYRK1A phosphorylates tau protein suggest that this kinase is also involved in tau protein phosphorylation in the human brain and contributes to neurofibrillary degeneration, and that this contribution might be enhanced in patients with DS. To explore this hypothesis, the brain tissue from 57 subjects including 16 control subjects, 21 patients with DS, and 20 patients with sporadic Alzheimer's disease (AD) was examined with two antibodies to the amino-terminus of DYRK1A (7F3 and G-19), as well as two polyclonal antibodies to its carboxy-terminus (X1079 and 324446). Western blots demonstrated higher levels of full-length DYRK1A in the brains of patients with DS when compared to control brains. Immunocytochemistry revealed that DYRK1A accumulates in neurofibrillary tangles (NFTs) in subjects with sporadic AD and in subjects with DS/AD. Overexpression of DYRK1A in patients with DS was associated with an increase in DYRK1A-positive NFTs in a gene dosage-dependent manner. Results support the hypothesis that overexpressed DYRK1A contributes to neurofibrillary degeneration in DS more significantly than in subjects with two copies of the DYRK1A gene and sporadic AD. Immunoreactivity with antibodies against DYRK1A not only in NFTs but also in granules in granulovacuolar degeneration and in corpora amylacea suggests that DYRK1A is involved in all three forms of degeneration and that overexpression of this kinase may contribute to the early onset of these pathologies in DS.
Wegiel
Jerzy
J
Department of Developmental Neurobiology, NYS Institute for Basic Research in Developmental Disabilities, 1050 Forest Hill Road, Staten Island, NY 10314, USA. J_Wegiel@msn.com
Dowjat
Karol
K
Kaczmarski
Wojciech
W
Kuchna
Izabela
I
Nowicki
Krzysztof
K
Frackowiak
Janusz
J
Mazur Kolecka
Bozena
B
Wegiel
Jarek
J
Silverman
Wayne P
WP
Reisberg
Barry
B
Deleon
Mony
M
Wisniewski
Thomas
T
Gong
Cheng-Xin
CX
Liu
Fei
F
Adayev
Tatyana
T
Chen-Hwang
Mo-Chou
MC
Hwang
Yu-Wen
YW
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism; D016022:Case-Control Studies; D004314:Down Syndrome / Q000378:metabolism* / Q000473:pathology*; D005260:Female; D018628:Gene Dosage; D005786:Gene Expression Regulation; D006801:Humans; D008297:Male; D008875:Middle Aged; D009410:Nerve Degeneration / Q000378:metabolism* / Q000473:pathology*; D009454:Neurofibrils / Q000378:metabolism* / Q000473:pathology*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D016875:tau Proteins / Q000378:metabolism; D000097603:Dyrk Kinases
D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D016875:tau Proteins; D000097603:Dyrk Kinases