The HDAC inhibitor 4b ameliorates the disease phenotype and transcriptional abnormalities in Huntington's disease transgenic mice

Abstract

Transcriptional dysregulation has emerged as a core pathologic feature of Huntington's disease (HD), one of several triplet-repeat disorders characterized by movement deficits and cognitive dysfunction. Although the mechanisms contributing to the gene expression deficits remain unknown, therapeutic strategies have aimed to improve transcriptional output via modulation of chromatin structure. Recent studies have demonstrated therapeutic effects of commercially available histone deacetylase (HDAC) inhibitors in several HD models; however, the therapeutic value of these compounds is limited by their toxic effects. Here, beneficial effects of a novel pimelic diphenylamide HDAC inhibitor, HDACi 4b, in an HD mouse model are reported. Chronic oral administration of HDACi 4b, beginning after the onset of motor deficits, significantly improved motor performance, overall appearance, and body weight of symptomatic R6/2 300Q transgenic mice. These effects were associated with significant attenuation of gross brain-size decline and striatal atrophy. Microarray studies revealed that HDACi 4b treatment ameliorated, in part, alterations in gene expression caused by the presence of mutant huntingtin protein in the striatum, cortex, and cerebellum of R6/2 300Q transgenic mice. For selected genes, HDACi 4b treatment reversed histone H3 hypoacetylation observed in the presence of mutant huntingtin, in association with correction of mRNA expression levels. These findings suggest that HDACi 4b, and possibly related HDAC inhibitors, may offer clinical benefit for HD patients and provide a novel set of potential biomarkers for clinical assessment.rologic disorder caused by a CAG repeat expansion within the coding region of the HD gene (Htt), resulting in a mutant protein (htt) with a lengthened polyglutamine tract (1). Mutant htt protein has been shown to disrupt transcription by multiple mechanisms, but it is unclear which are most important to pathology (2-4). By interacting with specific transcription factors, htt can alter the expression of clusters of genes controlled by those factors. For example, several genes driven by Sp1, which has been shown to interact with htt (5, 6), show decreased mRNA expression in human HD and in mouse models of HD (7). Alternatively, htt may have more global effects on transcription by disrupting core transcriptional machinery (8, 9) or by altering posttranslational modifications of histones, resulting in condensed chromatin structure (10-13). Understanding the basis for transcriptional dysregulation is important for choosing appropriate drug-discovery strategies.Manifestations of transcriptional dysregulation are evident from several gene-profiling studies, which have revealed alterations in the expression of large numbers of genes in the brains of different HD mouse models and in human subjects with HD (7, 14-16). Many of the expression changes in mouse models are observed in early stages of illness before the onset of symptoms, suggesting that gene expression alterations may be pathogenic.Because o...

HDAC inhibition imparts beneficial transgenerational effects in Huntington's disease mice via altered DNA and histone methylation

“…Our studies have shown that inhibitors selectively targeting HDAC1 and HDAC3 are beneficial in several different HD model systems (9)(10)(11). In particular, in vivo studies have shown that pharmacological inhibition of HDAC1 and HDAC3 led to improved disease-associated body weight loss, motor dysfunction, and cognitive decline in two different HD mouse models (9,11).…”

“…However, several microarray studies have demonstrated that HDAC inhibitors can cause both up-and down-regulation of gene expression patterns (11,15), suggesting that HDAC inhibition may alter the expression of other regulatory enzymes and/or cofactors, which subsequently act as activators or repressors of gene activity. Accumulating evidence suggests that many HDACs, including class I HDACs, can also deacetylate nonhistone proteins (16), which may contribute to their beneficial properties.…”

Epigenetic Mechanisms of Neurodegeneration in Huntington's Disease

“…Importantly, histone modifications, such as hypo-acetylation and hypermethylation, have been identified in HD patients, HD animal models, and HD cell line models [53][54][55][56]. Interestingly, the hypo-acetylation of histone is correlated with downregulations of genes in HD, and therapeutic inhibition of HDAC restores the acetylation level of histone and improves the neuropathology and the motor symptom in HD [56][57][58][59][60][61].…”

“…In cell models of HD, polyglutamine decreases histone acetylation, and HDAC inhibitors have been shown to reduce polyglutamine-induced toxicity [93]. HDAC inhibitors also improve the phenotypes of transgenic Drosophila and mouse models of HD [57,60,65,92,94]. A number of HDAC inhibitors are currently under development as therapeutics to target neurodegenerative diseases.…”

“…As the potency of phenylbutyrate is very low and high doses are required in patients, it is not an ideal therapeutic compound for HD patients. Thomas et al [60] reported that a novel pimelic diphenylamide HDAC inhibitor 4b (HDACi 4b) ameliorates the disease phenotype and transcriptional abnormalities in HD transgenic (R6/2) mice [60]. HDACi 4b treatment effectively restored acetylation of histone H3 and corrected mRNA expression levels in HD mice.…”