A selective inhibitor of histone deacetylase 3 prevents cognitive deficits and suppresses striatal CAG repeat expansions in Huntington’s disease mice

Abstract

Huntington’s disease (HD) is a neurodegenerative disorder whose major symptoms include progressive motor and cognitive dysfunction. Cognitive decline is a critical quality of life concern for HD patients and families. The enzyme histone deacetylase 3 (HDAC3) appears to be important in HD pathology by negatively regulating genes involved in cognitive functions. Furthermore, HDAC3 has been implicated in the aberrant transcriptional patterns that help cause disease symptoms in HD mice. HDAC3 also helps fuel CAG repeat expansions in human cells, suggesting that HDAC3 may power striatal expansions in the HTT gene thought to drive disease progression. This multifaceted role suggests that early HDAC3 inhibition offers an attractive mechanism to prevent HD cognitive decline and to suppress striatal expansions. This hypothesis was investigated by treating HdhQ111 knock-in mice with the HDAC3-selective inhibitor RGFP966. Chronic early treatment prevented long-term memory impairments and normalized specific memory-related gene expression in hippocampus. Additionally, RGFP966 prevented corticostriatal-dependent motor learning deficits, significantly suppressed striatal CAG repeat expansions, partially rescued striatal protein marker expression and reduced accumulation of mutant huntingtin oligomeric forms. These novel results highlight RGFP966 as an appealing multiple-benefit therapy in HD that concurrently prevents cognitive decline and suppresses striatal CAG repeat expansions.

Complex neuroprotective and neurotoxic effects of histone deacetylases

“…This interaction was found to coincide with the onset of motor deficits (Bardai et al 2013). 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).…”

“…, , ; Thomas ; Suelves et al . ). Alterations in histone acetylation and ensuing gene expression were implicated in these effects (Thomas et al .…”

“…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 . ). Genetic reduction in HDAC3 using Hdac3 (+/−) heterozygous mice has been reported, and was not found to ameliorate disease phenotypes when crossed with R6/2 transgenic mice (Moumne et al .…”

“…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). Genetic reduction in HDAC3 using Hdac3 (+/À) heterozygous mice has been reported, and was not found to ameliorate disease phenotypes when crossed with R6/2 transgenic mice (Moumne et al 2012).…”

IDO and Kynurenine Metabolites in Peripheral and CNS Disorders

“…Several of the disorders discussed above may be susceptible to epigenetic influences. The brains of patients with Huntington's disease exhibit evidence of alterations in methylation status (207,208) or acetylation status (209) and inhibition of a histone deacetylase may prevent the development of cognitive deficits as well as huntingtin expansion (210). Such changes may contribute significantly to the course of the disorder and its heritability, especially since DNA methylation has been shown to produce extension of the mutant CAG repeat sequence (211).…”