Histone Deacetylase Inhibition by Sodium Butyrate Chemotherapy Ameliorates the Neurodegenerative Phenotype in Huntington's Disease Mice

Abstract

The precise cause of neuronal death in Huntington's disease (HD) is unknown. Although no single specific protein-protein interaction of mutant huntingtin has emerged as the pathologic trigger, transcriptional dysfunction may contribute to the neurodegeneration observed in HD. Pharmacological treatment using the histone deacetylase inhibitor sodium butyrate to modulate transcription significantly extended survival in a dose-dependent manner, improved body weight and motor performance, and delayed the neuropathological sequelae in the R6/2 transgenic mouse model of HD. Sodium butyrate also increased histone and Specificity protein-1 acetylation and protected against 3-nitropropionic acid neurotoxicity. Microarray analysis showed increased expression of alpha- and beta-globins and MAP kinase phosphatase-1 in sodium butyrate-treated R6/2 mice, indicative of improved oxidative phosphorylation and transcriptional regulation. These findings strengthen the hypothesis that transcriptional dysfunction plays a role in the pathogenesis of HD and suggest that therapies aimed at modulating transcription may target early pathological events and provide clinical benefits to HD patients.

Acetyltransferases (HATs) as Targets for Neurological Therapeutics

“…However, the overexpression of PCAF was not sufficient to ameliorate the HD phenotype in transgenic flies, suggesting that therapeutic strategies aimed at increasing PCAF protein levels are likely ineffective in ameliorating HD pathology; notably, increasing the HAT activity of PCAF has not been tested, and other trials targeting PCAF activity are needed [86]. Increasing the acetylation of histones and non-histone proteins via the use of HDAC inhibitors also counteracts neurodegeneration [8,88,[99][100][101]. Intriguingly, McFarlan et al [96] also demonstrated that HDAC inhibition reestablished altered transcriptional levels in the striatum of the R6/2 mouse model, but only slightly improved H3ac binding to specific promoter, emphasizing the idea that the overall chromatin environment surrounding a gene would be more adapted to therapeutic targeting than simply increasing the acetylation of the histones.…”

Neural circuitry and neuroplasticity in mood disorders: Insights for novel therapeutic targets

“…In support of this, valproate and several other HDAC inhibitors have shown neuroprotective effects in animal models of cerebral ischemia, 190,191 Parkinson's disease, 192 and Huntington's disease. 193,194 Weaver and associates 195 demonstrated in rat pups that behaviorally programmed, persistent epigenomic alterations of a glucocorticoid receptor gene promoter in the hippocampus induced by certain styles of maternal behavior could be reversed by central infusion of an HDAC inhibitor. Tremolizzo and colleagues 196 found that hypermethylation of the reelin promoter and subsequent decrease of reelin expression, which have been suggested by recent studies to be present in BD and schizophrenia patients, were prevented by valproate in doses inhibitory to HDACs.…”

Epigenetic Mechanisms of Neurodegeneration in Huntington's Disease

“…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.…”

“…The toxicity of sodium butyrate is low, and it is well tolerated in both human and animal studies [95][96][97]. Sodium butyrate modulates epigenetic histone modifications, improves motor performance and neuropathologic sequelae, and significantly extends survival of transgenic HD (R6/2) mice [94].…”