McConoughey, S.J., Basso, M., Niatsetskaya, Z.V., Sleiman, S.F., Smirnova, N.A., Langley, B.C., Mahishi, L., Cooper, A.J., Antonyak, M.A., Cerione, R.A., Li, B., Starkov, A., Chaturvedi, R.K., Beal, M.F., Coppola, G., Geschwind, D.H., Ryu, H., Xia, L., Iismaa, S.E., Pallos, J., Pasternack, R., Hils, M., Fan, J., Raymond, L.A., Marsh, J.L., Thompson, L.M., Ratan, R.R. (2010). Inhibition of transglutaminase 2 mitigates transcriptional dysregulation in models of Huntington disease.  EMBO Mol. Med. 2(9): 349--370.

FBrf0211687

Research paper

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.

PMC3068019 (PMC) (EuropePMC)