期刊
EMBO MOLECULAR MEDICINE
卷 2, 期 9, 页码 349-370出版社
WILEY
DOI: 10.1002/emmm.201000084
关键词
transglutaminase; Huntington's disease; transcriptional dysregulation; mitochondrial bioenergetics; ZDON
资金
- Sheldon and Miriam Adelson Medical Research Foundation
- Hereditary Disease Foundation [HDF-24085]
- Huntington's Disease Society of America
- HighQ Foundation
- Cure Huntington Disease Initiative (CHDI)
- National Institutes of Health [P01 NIA AGO 14930, NS045283, NS52789]
Caused by a polyglutamine expansion in the huntingtin protein, Huntington's disease leads to stnatal degeneration via the transcriptional dysregulation of a number of genes, including those involved in mitochondnal 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-l alpha 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 mitochondnal 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 stnatal 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.
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