Title | Link between DYRK1A overexpression and several-fold enhancement of neurofibrillary degeneration with 3-repeat tau protein in Down syndrome. |
Publication Type | Journal Article |
Year of Publication | 2011 |
Authors | Wegiel J, Kaczmarski W, Barua M, Kuchna I, Nowicki K, Wang K-C, Wegiel J, Yang SMa, Frackowiak J, Mazur-Kolecka B, Silverman WP, Reisberg B, Monteiro I, de Leon M, Wisniewski T, Dalton A, Lai F, Hwang Y-W, Adayev T, Liu F, Iqbal K, Iqbal I-G, Gong C-X |
Journal | J Neuropathol Exp Neurol |
Volume | 70 |
Issue | 1 |
Pagination | 36-50 |
Date Published | 2011 Jan |
ISSN | 1554-6578 |
Keywords | Adult, Aged, Aged, 80 and over, Animals, Cattle, Down Syndrome, Female, Gene Dosage, Gene Expression Regulation, Enzymologic, Humans, Male, Mice, Middle Aged, Nerve Degeneration, Neurofibrillary Tangles, Phenotype, Protein Serine-Threonine Kinases, Protein-Tyrosine Kinases, Rats, tau Proteins, Trinucleotide Repeats |
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 |
Alternate Journal | J Neuropathol Exp Neurol |
PubMed ID | 21157379 |
PubMed Central ID | PMC3083064 |
Grant List | N01-HD-4-3383 / HD / NICHD NIH HHS / United States R01 HDO43960 / / PHS HHS / United States N01-HD-4-3368 / HD / NICHD NIH HHS / United States R01 AG003051 / AG / NIA NIH HHS / United States P01-HDO35897 / / PHS HHS / United States AG08051 / AG / NIA NIH HHS / United States R01 AG027429 / AG / NIA NIH HHS / United States R01 HD043960-05 / HD / NICHD NIH HHS / United States P30 AG008051 / AG / NIA NIH HHS / United States R01 HD043960 / HD / NICHD NIH HHS / United States HDO38295 / / PHS HHS / United States AG03051 / AG / NIA NIH HHS / United States |
Related Institute:
Brain Health Imaging Institute (BHII)