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

摘要: Caused by a polyglutamine expansion in the huntingtin protein, Huntington's disease leads to striatal degeneration via transcriptional dysregulation of number genes, including those involved mitochondrial biogenesis. Here we show that transglutaminase 2, which is upregulated HD, exacerbates acting as selective corepressor nuclear genes; 2 interacts directly with histone H3 nucleus. In cellular model inhibition de-repressed two established regulators function, PGC-1α and cytochrome c reversed susceptibility human HD cells toxin, 3-nitroproprionic acid; however, protection mediated was not associated improved bioenergetics. A gene microarray analysis indicated normalized expression only genes but also 40% are dysregulated neurons, chaperone genes. Moreover, attenuated Drosophila protected mouse neurons from excitotoxicity. Altogether these findings demonstrate TG broadly corrects defines novel HDAC-independent epigenetic strategy for treating neurodegeneration.