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Inhibition of transglutaminase 2 mitigates transcriptional dysregulation in models of Huntington disease.

EMBO molecular medicine | Sep 7, 2010

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.

Pubmed ID: 20665636 RIS Download

Mesh terms: 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

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Associated grants

  • Agency: NIA NIH HHS, Id: P01 AG014930-04
  • Agency: NINDS NIH HHS, Id: NS045283
  • Agency: NIA NIH HHS, Id: P01 NIA AG014930
  • Agency: NINDS NIH HHS, Id: R01 NS052789-01A1
  • Agency: NINDS NIH HHS, Id: R01 NS045283
  • Agency: NINDS NIH HHS, Id: R01 NS052789
  • Agency: NINDS NIH HHS, Id: R21 NS072793
  • Agency: NINDS NIH HHS, Id: R01 NS045283-01
  • Agency: NIGMS NIH HHS, Id: R01 GM061762
  • Agency: NIA NIH HHS, Id: P01 AG014930
  • Agency: NINDS NIH HHS, Id: NS52789

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