Selective histone deacetylase (HDAC) inhibition imparts beneficial effects in Huntington's disease mice: implications for the ubiquitin–proteasomal and autophagy systems

Abstract

We previously demonstrated that the histone deacetylase (HDAC) inhibitor, 4b, which preferentially targets HDAC1 and HDAC3, ameliorates Huntington's disease (HD)-related phenotypes in different HD model systems. In the current study, we investigated extensive behavioral and biological effects of 4b in N171-82Q transgenic mice and further explored potential molecular mechanisms of 4b action. We found that 4b significantly prevented body weight loss, improved several parameters of motor function and ameliorated Huntingtin (Htt)-elicited cognitive decline in N171-82Q transgenic mice. Pathways analysis of microarray data from the mouse brain revealed gene networks involving post-translational modification, including protein phosphorylation and ubiquitination pathways, associated with 4b drug treatment. Using real-time qPCR analysis, we validated differential regulation of several genes in these pathways by 4b, including Ube2K, Ubqln, Ube2e3, Usp28 and Sumo2, as well as several other related genes. Additionally, 4b elicited increases in the expression of genes encoding components of the inhibitor of kappaB kinase (IKK) complex. IKK activation has been linked to phosphorylation, acetylation and clearance of the Htt protein by the proteasome and the lysosome, and accordingly, we found elevated levels of phosphorylated endogenous wild-type (wt) Htt protein at serine 16 and threonine 3, and increased AcK9/pS13/pS16 immunoreactivity in cortical samples from 4b-treated mice. We further show that HDAC inhibitors prevent the formation of nuclear Htt aggregates in the brains of N171-82Q mice. Our findings suggest that one mechanism of 4b action is associated with the modulation of the ubiquitin-proteasomal and autophagy pathways, which could affect accumulation, stability and/or clearance of important disease-related proteins, such as Htt.

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

“…S2). These results are highly similar to our previous studies using HDACi 4b (9). However, we did not observe any significant transgenerational effects of RGFP966 on the F1 generation of N171-82Q transgenic mice (i.e., the offspring of RGFP966-treated fathers) (Fig.…”

“…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). These findings are consistent with other studies showing beneficial effects of broadly acting HDAC inhibitors in HD mouse models (12)(13)(14).…”

“…We have previously shown that HDAC1/3-targeting HDAC inhibitors show therapeutic efficacy in HD mouse models, in association with elevated histone acetylation levels (9)(10)(11). To identify gene expression changes associated with altered histone acetylation levels, we performed microarray analysis on skeletal muscle samples from N171-82Q HD transgenic mice treated with the HDAC1/3-targeting compound HDACi 4b and reanalyzed microarray data from brain samples of HDACi 4b-treated R6/2 transgenic mice from our earlier studies (11).…”

Epigenetic Mechanisms of Neurodegeneration in Huntington's Disease

“…HDACi 4b treatment effectively restored acetylation of histone H3 and corrected mRNA expression levels in HD mice. HDACi 4b also significantly improved body weight and several parameters of motor function, and ameliorated cognitive decline in N171-82Q transgenic mice [101]. Interestingly, HDACi 4b treatment modulated gene networks involving post-translational modification, including protein phosphorylation and ubiquitination pathways.…”

Class I HDAC imaging using [3H]CI-994 autoradiography

“…[5][6][7] The utility of HDACi in treating central nervous system (CNS) disorders is less clear; 8 however, abnormal expression levels of class-I HDACs have been correlated with several CNS disorders, including Huntington disease, 9 amyotrophic lateral sclerosis (ALS), [10][11][12] psychiatric disorders, 13 and Alzheimer disease.…”