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

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

Authors

  • McConoughey SJ
  • Basso M
  • Niatsetskaya ZV
  • Sleiman SF
  • Smirnova NA
  • Langley BC
  • Mahishi L
  • Cooper AJ
  • Antonyak MA
  • Cerione RA
  • Li B
  • Starkov A
  • Chaturvedi RK
  • Beal MF
  • Coppola G
  • Geschwind DH
  • Ryu H
  • Xia L
  • Iismaa SE
  • Pallos J
  • Pasternack R
  • Hils M
  • Fan J
  • Raymond LA
  • Marsh JL
  • Thompson LM
  • Ratan RR

Journal

EMBO molecular medicine

Publication Data

September 7, 2010

Associated Grants

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

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
  • Promoter Regions, Genetic
  • Propionates
  • Transcription Factors
  • Transcription, Genetic
  • Transglutaminases