Overexpression of Dyrk1A contributes to neurofibrillary degeneration in Down syndrome

FASEB J. 2008 Sep;22(9):3224-33. doi: 10.1096/fj.07-104539. Epub 2008 May 28.

Abstract

Adults with Down syndrome (DS) develop Alzheimer neurofibrillary degeneration in the brain, but the underlying molecular mechanism is unknown. Here, we report that the presence of an extra copy of the dual-specificity tyrosine-phosphorylated and regulated kinase 1A (Dyrk1A) gene due to trisomy 21 resulted in overexpression of Dyrk1A and elevated kinase activity in DS brain. Dyrk1A phosphorylated tau at several sites, and these sites were hyperphosphorylated in adult DS brains. Phosphorylation of tau by Dyrk1A primed its further phosphorylation by glycogen synthase kinase-3beta (GSK-3beta). Dyrk1A-induced tau phosphorylation inhibited tau's biological activity and promoted its self-aggregation. In Ts65Dn mouse brain, an extra copy of the Dyrk1A gene caused increased expression and activity of Dyrk1A and resulted in increased tau phosphorylation. These findings strongly suggest a novel mechanism by which the overexpression of Dyrk1A in DS brain causes neurofibrillary degeneration via hyperphosphorylating tau.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Animals
  • Down Syndrome / pathology*
  • Down Syndrome / physiopathology
  • Female
  • Gene Expression Regulation, Developmental
  • Glycogen Synthase Kinase 3 / metabolism
  • Glycogen Synthase Kinase 3 beta
  • Humans
  • Male
  • Mice
  • Middle Aged
  • Nerve Degeneration / pathology*
  • Neurofibrillary Tangles / pathology*
  • Phosphorylation
  • Protein-Serine-Threonine Kinases / biosynthesis*
  • Protein-Serine-Threonine Kinases / physiology
  • Protein-Tyrosine Kinases / biosynthesis*
  • Protein-Tyrosine Kinases / physiology
  • tau Proteins / metabolism

Substances

  • MAPT protein, human
  • tau Proteins
  • Dyrk kinase
  • Protein-Tyrosine Kinases
  • GSK3B protein, human
  • Glycogen Synthase Kinase 3 beta
  • Gsk3b protein, mouse
  • Protein-Serine-Threonine Kinases
  • Glycogen Synthase Kinase 3