Link between DYRK1A overexpression and several-fold enhancement of neurofibrillary degeneration with 3-repeat tau protein in down syndrome

Jerzy Wegiel, Wojciech Kaczmarski, Madhabi Barua, Izabela Kuchna, Krzysztof Nowicki, Kuo Chiang Wang, Jarek Wegiel, Shuang Yang, Janusz Frackowiak, Bozena Mazur-Kolecka, Wayne P Silverman, Barry Reisberg, Isabel Monteiro, Mony De Leon, Thomas Wisniewski, Arthur Dalton, Florence Lai, Yu Wen Hwang, Tatyana Adayev, Fei LiuKhalid Iqbal, Inge Grundke Iqbal, Cheng Xin Gong

Research output: Contribution to journalArticle

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 ofASF by overexpressed DYRK1A may contribute to alternative splicing of exon 10, increased expression of 3R tau, and early onset of neurofibrillary degeneration in DS.

Original languageEnglish (US)
Pages (from-to)36-50
Number of pages15
JournalJournal of Neuropathology and Experimental Neurology
Volume70
Issue number1
DOIs
Publication statusPublished - Jan 2011

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Keywords

  • 3-Repeat tau
  • Alternative splicing factor
  • Alzheimer disease
  • Down syndrome
  • DYRK1A
  • Neurofibrillary degeneration

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Clinical Neurology
  • Neurology
  • Cellular and Molecular Neuroscience

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