Abstract
Histone deacetylases (HDACs) enzymes, which affect the acetylation status of histones and other important cellular proteins, have been recognized as potentially useful therapeutic targets for a broad range of human disorders. Emerging studies have demonstrated that different types of HDAC inhibitors show beneficial effects in various experimental models of neurological disorders. HDAC enzymes comprise a large family of proteins, with18 HDAC enzymes currently identified in humans. Hence, an important question for HDAC inhibitor therapeutics is which HDAC enzyme(s) is/are important for the amelioration of disease phenotypes, as it has become clear that individual HDAC enzymes play different biological roles in the brain. This review will discuss evidence supporting the involvement of HDAC1 and HDAC3 in polyglutamine disorders, including Huntington’s disease, and the use of HDAC1- and HDAC3-selective HDAC inhibitors as therapeutic intervention for these disorders. Further, while HDAC inhibitors are known alter chromatin structure resulting in changes in gene transcription, understanding the exact mechanisms responsible for the preclinical efficacy of these compounds remains a challenge. The potential chromatin-related and non-chromatin-related mechanisms of action of selective HDAC inhibitors will also be discussed.
Highlights
A growing body of literature suggests that epigenetic dysregulation is a key pathogenic feature of many polyglutamine disorders [1,2,3]
The Histone deacetylases (HDACs) comprise a large family of proteins, with18 HDAC enzymes having been identified in humans [5], and studies over the past five years have demonstrated that individual HDAC enzymes play vastly different roles in the CNS
RGFP136 was found to significantly enhance persistent long-term memory in normal rats [111], suggesting improvement in cognitive function under normal conditions. Another HDAC3-selective inhibitor, RGFP966, was tested in the N171-82Q transgenic mouse model, where it significantly prevented body weight loss, improved several parameters of motor function and ameliorated Huntingtin-elicited cognitive decline in N171-82Q transgenic mice [112]. These findings demonstrate that class I HDAC inhibitors are effective in suppressing pathogenic symptoms in various polyglutamine models with HDAC3-selective compounds exhibiting some of the strongest effects
Summary
A growing body of literature suggests that epigenetic dysregulation is a key pathogenic feature of many polyglutamine disorders [1,2,3]. HDAC inhibitors; the clinical use of these broadly-acting compounds for neurodegenerative disorders is limited by their known toxicity, it is becoming clear that inhibitors with subtype-selectivity may prove to be more beneficial for targeting neurological disease symptoms and minimizing harmful side effects [4]. The HDACs comprise a large family of proteins, with HDAC enzymes having been identified in humans [5], and studies over the past five years have demonstrated that individual HDAC enzymes play vastly different roles in the CNS. Recent findings have demonstrated that class I-specific and HDAC1/HDAC3-selective HDAC inhibitors are effective in suppressing pathogenic symptoms in various model systems. This review will summarize the involvement of HDACs 1 and 3 in HD, and other polyglutamine disorders, providing a basis for the use of selective HDAC inhibitors targeting these subtypes for therapeutic purposes
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