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,...
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| Other Authors: | , , , , , |
| Format: | article |
| Published: |
2010
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| Online Access: | http://hdl.handle.net/10725/6142 http://dx.doi.org/10.1002/emmm.201000084 http://libraries.lau.edu.lb/research/laur/terms-of-use/articles.php http://embomolmed.embopress.org/content/2/9/349.short |
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| Summary: | 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‐1α 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 |
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