Publication Type Academic Article
Authors Wegiel J, Kaczmarski W, Barua M, Kuchna I, Nowicki K, Wang K, Wegiel J, Yang S, Frackowiak J, Mazur-Kolecka B, Silverman W, Reisberg B, Monteiro I, de Leon M, Wisniewski T, Dalton A, Lai F, Hwang Y, Adayev T, Liu F, Iqbal K, Iqbal I, Gong C
Journal J Neuropathol Exp Neurol
Volume 70
Issue 1
Pagination 36-50
Date Published 01/01/2011
ISSN 1554-6578
Keywords Down Syndrome, Gene Expression Regulation, Enzymologic, Nerve Degeneration, Neurofibrillary Tangles, Protein Serine-Threonine Kinases, Protein-Tyrosine Kinases, tau Proteins
Abstract Triplication of chromosome 21 in Down syndrome (DS) results in overexpression of the minibrain kinase/dual-specificity tyrosine phosphorylated and regulated kinase 1A gene (DYRK1A). DYRK1A phosphorylates cytoplasmic tau protein and appears in intraneuronal neurofibrillary tangles (NFTs). We have previously shown significantly more DYRK1A-positive NFTs in DS brains than in sporadic Alzheimer disease (AD) brains. This study demonstrates a gene dosage-proportional increase in the level of DYRK1A in DS in the cytoplasm and the cell nucleus, and enhanced cytoplasmic and nuclear immunoreactivity of DYRK1A in DS. The results suggest that overexpressed DYRK1A may alter both phosphorylation of tau and alternative splicing factor (ASF). Two-dimensional electrophoresis revealed modification of ASF phosphorylation in DS/AD and AD in comparison to controls. Altered phosphorylation of ASF by overexpressed nuclear DYRK1A may contribute to the alternative splicing of the tau gene and an increase by 2.68 × of the 3R/4R ratio in DS/AD, and a several-fold increase in the number of 3R tau-positive NFTs in DS/AD subjects compared with that in sporadic AD subjects. These data support the hypothesis that phosphorylation of ASF by overexpressed DYRK1A may contribute to alternative splicing of exon 10, increased expression of 3R tau, and early onset of neurofibrillary degeneration in DS.
DOI 10.1097/NEN.0b013e318202bfa1
PubMed ID 21157379
PubMed Central ID PMC3083064
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