Histone deacetylase inhibitors as therapeutics for polyglutamine disorders

Transcriptional dysregulation is part of the pathogenic mechanism that underlies neuronal dysfunction in polyglutamine repeat diseases such as Huntington's disease (HD). Microarray experiments show that the expression of a subset of genes is robustly altered in mouse models of HD and in the brains of patients with HD.Histone acetyltransferases (HATs) and histone deacetylases (HDACs) are enzymes that control transcription by acetylating and deacetylating histones, thereby changing the conformation of chromatin structure.Expanded polyglutamine repeat proteins adopt aberrant interactions with HATs and HDACs as well as other transcription factors, co-activators and co-repressors owing to conformational changes caused by the polyglutamine stretch within the mutant protein.Of the four classes of HDAC enzyme, class I is ubiquitously expressed and class II is highly expressed in muscle, heart and brain.In addition to deacetylating histones, HDACs also modify non-histone proteins such as the tumour suppressor p53 and heat shock protein 90 (HSP90), both of which are implicated in HD pathogenesis.Compounds that inhibit these class I and II HDACs are in clinical trials for the treatment of many types of cancer. These drugs are currently being tested in preclinical trials using mouse models of polyglutamine repeat disease.One HDAC inhibitor, phenylbutyrate, is in phase II clinical trials for HD, and alterations in blood biomarker expression after treatment look promising.