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Inhibition of transglutaminase 2 mitigates transcriptional dysregulation in models of Huntington's disease

  • Author(s): McConoughey, SJ
  • Basso, M
  • Niatsetskaya, ZV
  • Sleiman, SF
  • Smirnova, NA
  • Langley, BC
  • Mahishi, L
  • Cooper, AJL
  • Antonyak, MA
  • Cerione, RA
  • Li, B
  • Starkov, A
  • Chaturvedi, RK
  • Bea, 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
  • et al.

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-1a 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 onlymitochondrial 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 protectedmouse 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. © 2010 EMBO Molecular Medicine.

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