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Mechanisms of Disease: histone modifications in Huntington's disease

Nature Clinical Practice Neurology volume 2, pages 330–338 (2006)Cite this article

Abstract

Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by a polyglutamine repeat expansion within the huntingtin protein. HD is characterized by problems with movement, cognition and behavioral functioning, and there is currently no effective treatment. Although multiple pathologic mechanisms have been proposed, the exact mechanism by which mutant huntingtin causes neuronal dysfunction is not known. Recent studies demonstrating altered messenger RNA expression point to transcriptional dysregulation as a central mechanism. The control of eukaryotic gene expression depends on the modification of histone proteins associated with specific genes, with histone acetylation playing a crucial role. Studies in numerous HD models have shown that mutant huntingtin alters histone acetyltransferase activity, and indicate that aberrant activity of this enzyme might be an underlying mechanism of transcriptional dysregulation in HD. Furthermore, recent studies have shown a therapeutic role for histone deacetylase inhibitors in a number of HD models. In this review, we summarize the current state of knowledge regarding the status of histones in HD. In addition, we discuss how these histone modifications not only lead to pathogenesis, but might also provide a novel therapeutic strategy for treating this devastating disease.

Key Points

  • Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by a polyglutamine repeat expansion within the huntingtin (Htt) protein

  • Although Htt is expressed throughout the body, HD principally affects the brain

  • There is strong evidence that transcriptional dysregulation is an important underlying mechanism in HD pathogenesis

  • Mutant Htt interacts with numerous transcription factors, providing a mechanism through which this protein can interfere with normal transcriptional activity

  • Gene expression is regulated through the action of transcription factors that alter chromatin structure through the recruitment of histone-modifying enzymes

  • Histones are hypoacetylated in mouse models of HD, and there are strong indications that histone deacetylase inhibitors might be of therapeutic benefit in this condition

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Figure 1: Known modifications of human histone H3.
Figure 2: Schematic representation of histone acetylation.

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Acknowledgements

This work was supported by NIH grants NS045242 and NS038106, the Huntington's Disease Society of America Coalition for the Cure, the Glendorn Foundation, the Hereditary Disease Foundation, and the HighQ Foundation. Because of space limitations, we were unable to include the contributions of many other scientists who have made significant contributions in this area.

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Authors and Affiliations

  1. research fellow at the MassGeneral Institute for Neurodegenerative Disease,

    Ghazaleh Sadri-Vakili & Jang-Ho J Cha

  2. associate professor of neurology at Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA

    Ghazaleh Sadri-Vakili & Jang-Ho J Cha

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  1. Ghazaleh Sadri-Vakili
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Correspondence to Jang-Ho J Cha.

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Sadri-Vakili, G., Cha, JH. Mechanisms of Disease: histone modifications in Huntington's disease. Nat Rev Neurol 2, 330–338 (2006). https://doi.org/10.1038/ncpneuro0199

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