SAHA Decreases HDAC 2 and 4 Levels In Vivo and Improves Molecular Phenotypes in the R6/2 Mouse Model of Huntington's Disease

Abstract

Huntington's disease (HD) is a progressive neurological disorder for which there are no disease-modifying treatments. Transcriptional dysregulation is a major molecular feature of HD, which significantly contributes to disease progression. Therefore, the development of histone deacetylase (HDAC) inhibitors as therapeutics for HD has been energetically pursued. Suberoylanilide hydroxamic acid (SAHA) – a class I HDAC as well an HDAC6 inhibitor, improved motor impairment in the R6/2 mouse model of HD. Recently it has been found that SAHA can also promote the degradation of HDAC4 and possibly other class IIa HDACs at the protein level in various cancer cell lines. To elucidate whether SAHA is a potent modifier of HDAC protein levels in vivo, we performed two independent mouse trials. Both WT and R6/2 mice were chronically treated with SAHA and vehicle. We found that prolonged SAHA treatment causes the degradation of HDAC4 in cortex and brain stem, but not hippocampus, without affecting its transcript levels in vivo. Similarly, SAHA also decreased HDAC2 levels without modifying the expression of its mRNA. Consistent with our previous data, SAHA treatment diminishes Hdac7 transcript levels in both wild type and R6/2 brains and unexpectedly was found to decrease Hdac11 in R6/2 but not wild type. We investigated the effects of SAHA administration on well-characterised molecular readouts of disease progression. We found that SAHA reduces SDS-insoluble aggregate load in the cortex and brain stem but not in the hippocampus of the R6/2 brains, and that this was accompanied by restoration of Bdnf cortical transcript levels.

An impaired metabolism of nucleotides underpins a novel mechanism of cardiac remodeling leading to Huntington's disease related cardiomyopathy

“…The reverse transcription reaction was performed using MMLV superscript reverse transcriptase (Invitrogen, USA) and random hexamers (Sigma, USA), as described elsewhere [17]. All Taqman qPCR reactions (Cycler DNA Engine, Peltier Thermal Cycler, Bio-Rad, USA) were performed as described previously.…”

“…Estimation of mRNA copy number was determined in triplicate for each RNA sample by comparison with the geometric mean of three endogenous housekeeping genes (Primer Design, UK), as described [17].…”

Epigenetic Mechanisms of Neurodegeneration in Huntington's Disease

“…Suberoylanilide hydroxamic acid and sodium butyrate are the first compounds that provide the efficacy of HDAC inhibition and histone modification in HD transgenic mice [91,92]. These pioneering studies ignited the rationale for beginning clinical testing of HDAC inhibitors in humans with HD.…”

“…These pioneering studies ignited the rationale for beginning clinical testing of HDAC inhibitors in humans with HD. Enhancement of memory formation is found in mice treated with sodium butyrate or suberoylanilide hydroxamic acid, or subjected to genetic knockout of the HDAC2 gene [92]. In the case of CBP deficiency and HAT deletion mutant animal models, HDAC inhibitors also improve memory and behavioral symptoms.…”

“…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.…”