Involvement of HDAC1 and HDAC3 in the Pathology of Polyglutamine Disorders: Therapeutic Implications for Selective HDAC1/HDAC3 Inhibitors

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.

Complex neuroprotective and neurotoxic effects of histone deacetylases

“…Consistent with these results are those showing that administration of chemical inhibitors selective for HDAC1/HDAC3, or HDAC3 alone, reduced neuropathology and improved behavioral performance in R6/2 and N171-82Q transgenic mouse models of Huntington's disease (Thomas et al 2008;Jia et al 2012Jia et al , 2015Jia et al , 2016Thomas 2014;Suelves et al 2017). Alterations in histone acetylation and ensuing gene expression were implicated in these effects (Thomas et al 2008;Jia et al 2012Jia et al , 2015Jia et al , 2016Thomas 2014). Protective effects of an HDAC3-selective inhibitor, RGFP966, in yet another Huntington's disease mouse model, Hdh Q111 knock-in mice, was also demonstrated by a different laboratory (Suelves et al 2017).…”

“…; Jia et al . , , ; Thomas ). Protective effects of an HDAC3‐selective inhibitor, RGFP966, in yet another Huntington's disease mouse model, Hdh Q111 knock‐in mice, was also demonstrated by a different laboratory (Suelves et al .…”

Class I and IIa Histone Deacetylases Have Opposite Effects on Sclerostin Gene Regulation

“…7A) and did not relieve PTH-induced SOST repression (data not shown) indicating that HDAC5 catalytic activity is not required for its regulation of Sost expression. In contrast, the pan-HDI TSA (46,47) (46,47,49,50). In contrast to TSA and apicidin, MS-275 did not inhibit SOST expression, but showed a bell-shaped about 2-fold stimulation with a maximum at 1 M. A similar response was obtained with MGCD0103 (51,52), another potent HDAC1 inhibitor (data not shown).…”

Sin3a regulates epithelial progenitor cell fate during lung development

“…Although Hdac activity is clearly central to chromatin remodeling, the full activity and genome targeting of Hdacs requires their assembly into multi-subunit complexes. For example, the recruitment of the Hdac1/2 complex into the vicinity of specific target genes is determined by the association of Hdac1/2 with specific co-repressor proteins/complexes such as NuRD, REST/CoREST or Sin3, which mediates the interaction with other subunits and sequence-specific transcription factors (Thomas, 2014). However, the role of specific co-repressor proteins in cell fate decisions during embryonic development and postnatal tissue homeostasis remains poorly understood.…”