The role of overexpressed DYRK1A protein in the early onset of neurofibrillary degeneration in Down syndrome

Jerzy Wegiel, Karol Dowjat, Wojciech Kaczmarski, Izabela Kuchna, Krzysztof Nowicki, Janusz Frackowiak, Bozena Mazur Kolecka, Jarek Wegiel, Wayne P. Silverman, Barry Reisberg, Mony de Leon, Thomas Wisniewski, Cheng Xin Gong, Fei Liu, Tatyana Adayev, Mo Chou Chen-Hwang, Yu Wen Hwang

Research output: Contribution to journalReview article

Abstract

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.

Original languageEnglish (US)
Pages (from-to)391-407
Number of pages17
JournalActa neuropathologica
Volume116
Issue number4
DOIs
StatePublished - Aug 13 2008

Keywords

  • Alzheimer's disease
  • Corpora amylacea
  • Down syndrome
  • Granulovacuolar degeneration
  • Minibrain kinase DYRK1A
  • Neurofibrillary degeneration

ASJC Scopus subject areas

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

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  • Cite this

    Wegiel, J., Dowjat, K., Kaczmarski, W., Kuchna, I., Nowicki, K., Frackowiak, J., Mazur Kolecka, B., Wegiel, J., Silverman, W. P., Reisberg, B., de Leon, M., Wisniewski, T., Gong, C. X., Liu, F., Adayev, T., Chen-Hwang, M. C., & Hwang, Y. W. (2008). The role of overexpressed DYRK1A protein in the early onset of neurofibrillary degeneration in Down syndrome. Acta neuropathologica, 116(4), 391-407. https://doi.org/10.1007/s00401-008-0419-6