Mechanisms of Disease: histone modifications in Huntington's disease

Transcriptional dysregulation is proposed to have an important role in the pathogenesis of Huntington's disease, and recent studies have implicated abnormal modifications of histone proteins in this process. Sadri-Vakili and Jang-Ho Cha review human and animal studies that have provided evidence for such a mechanism, and discuss the therapeutic potential of histone deacetylase inhibitors in Huntington's disease. 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.