Inhibition of transglutaminase 2 mitigates transcriptional dysregulation in models of Huntington disease. Academic Article uri icon

Overview

MeSH

  • Amino Acid Sequence
  • Animals
  • Cell Line, Tumor
  • Cytochromes c
  • Disease Models, Animal
  • Drosophila
  • Energy Metabolism
  • Enzyme Inhibitors
  • Heat-Shock Proteins
  • Histones
  • Humans
  • Mice
  • Mitochondria
  • Nitro Compounds
  • Peptides
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Promoter Regions, Genetic
  • Propionates
  • Transcription Factors

MeSH Major

  • GTP-Binding Proteins
  • Huntington Disease
  • Transcription, Genetic
  • Transglutaminases

abstract

  • Caused by a polyglutamine expansion in the huntingtin protein, Huntington's disease leads to striatal degeneration via the transcriptional dysregulation of a number of genes, including those involved in mitochondrial biogenesis. Here we show that transglutaminase 2, which is upregulated in HD, exacerbates transcriptional dysregulation by acting as a selective corepressor of nuclear genes; transglutaminase 2 interacts directly with histone H3 in the nucleus. In a cellular model of HD, transglutaminase inhibition de-repressed two established regulators of mitochondrial function, PGC-1alpha and cytochrome c and reversed susceptibility of human HD cells to the mitochondrial toxin, 3-nitroproprionic acid; however, protection mediated by transglutaminase inhibition was not associated with improved mitochondrial bioenergetics. A gene microarray analysis indicated that transglutaminase inhibition normalized expression of not only mitochondrial genes but also 40% of genes that are dysregulated in HD striatal neurons, including chaperone and histone genes. Moreover, transglutaminase inhibition attenuated degeneration in a Drosophila model of HD and protected mouse HD striatal neurons from excitotoxicity. Altogether these findings demonstrate that selective TG inhibition broadly corrects transcriptional dysregulation in HD and defines a novel HDAC-independent epigenetic strategy for treating neurodegeneration.

publication date

  • September 2010

has subject area

  • Amino Acid Sequence
  • Animals
  • Cell Line, Tumor
  • Cytochromes c
  • Disease Models, Animal
  • Drosophila
  • Energy Metabolism
  • Enzyme Inhibitors
  • GTP-Binding Proteins
  • Heat-Shock Proteins
  • Histones
  • Humans
  • Huntington Disease
  • Mice
  • Mitochondria
  • Nitro Compounds
  • Peptides
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Promoter Regions, Genetic
  • Propionates
  • Transcription Factors
  • Transcription, Genetic
  • Transglutaminases

Research

keywords

  • Journal Article

Identity

Language

  • eng

PubMed Central ID

  • PMC3068019

Digital Object Identifier (DOI)

  • 10.1002/emmm.201000084

PubMed ID

  • 20665636

Additional Document Info

start page

  • 349

end page

  • 370

volume

  • 2

number

  • 9