Mutations in the protein huntingtin that greatly expand the number of glutamine residues in the NH2-terminal polyglutamine tract are responsible for causing Huntington's disease. Now, Steffan et al. may have identified a mechanism by which the modified protein causes the neurodegeneration characteristic of the disease: expansion of the polyglutamine repeats in mutant huntingtin inhibits the histone acetylase functions of CREB-binding protein (CBP) and P/CAF (p300/CBP-associated protein). The NH2-terminal fragment of mutant huntingtin strongly inhibited the acetylation of histones H3 and H4 by CBP, p300, and P/CAF, in vitro and in vivo. This effect was reversed, in vivo, in the presence of the butyrate, a histone deacetylase inhibitor. Transgenic flies that expressed a fragment of huntingtin containing a greatly expanded glutamine tract or that made a peptide consisting solely of polyglutamine underwent neurodegeneration, as measured by the disrupted arrangement of ommatidia in the eye. However, the addition of histone deacetylase (HDAC) inhibitors into the fly food strongly reduced the neurodegeneration and prolonged the life-span of the transgenic flies. A protective effect was even observed when transgenic flies that already exhibited neurodegeneration were fed HDAC inhibitors, suggesting that treatment with HDAC inhibitors might be beneficial at various stages of the disease. Transgenic flies that also carried a partial mutation of Sin3A, a component of HDAC complexes, exhibited increased life-spans and lessened neurodegeneration. These results indicate that the most damaging effects of Huntington's disease might be ameliorated by the use of HDAC inhibitors or compounds that directly increase the enzymatic function of available histone acetylases. See the News & Views by Bates for a particularly useful overview.
J. S. Steffan, L. Bodai, J. Pallos, M. Poelman, A. McCampbell, B. L. Apostol, A. Kazantsev, E. Schmidt, Y.-z. Zhu, M. Greenwald, R. Kurokawa, D. E. Housman, G. R. Jackson, J. L. Marsh, L. M. Thompson, Histone deacetylase inhibitors arrest polyglutamine-dependent neurodegeneration in Drosophila. Nature 413, 739-743 (2001). [Online Journal]
G. P. Bates, Exploiting expression. Nature 413, 691-694 (2001). [Online Journal]