Genetic Knock-Down of HDAC7 Does Not Ameliorate Disease Pathogenesis in the R6/2 Mouse Model of Huntington's Disease

Abstract

Huntington's disease (HD) is an inherited, progressive neurological disorder caused by a CAG/polyglutamine repeat expansion, for which there is no effective disease modifying therapy. In recent years, transcriptional dysregulation has emerged as a pathogenic process that appears early in disease progression. Administration of histone deacetylase (HDAC) inhibitors such as suberoylanilide hydroxamic acid (SAHA) have consistently shown therapeutic potential in models of HD, at least partly through increasing the association of acetylated histones with down-regulated genes and by correcting mRNA abnormalities. The HDAC enzyme through which SAHA mediates its beneficial effects in the R6/2 mouse model of HD is not known. Therefore, we have embarked on a series of genetic studies to uncover the HDAC target that is relevant to therapeutic development for HD. HDAC7 is of interest in this context because SAHA has been shown to decrease HDAC7 expression in cell culture systems in addition to inhibiting enzyme activity. After confirming that expression levels of Hdac7 are decreased in the brains of wild type and R6/2 mice after SAHA administration, we performed a genetic cross to determine whether genetic reduction of Hdac7 would alleviate phenotypes in the R6/2 mice. We found no improvement in a number of physiological or behavioral phenotypes. Similarly, the dysregulated expression levels of a number of genes of interest were not improved suggesting that reduction in Hdac7 does not alleviate the R6/2 HD-related transcriptional dysregulation. Therefore, we conclude that the beneficial effects of HDAC inhibitors are not predominantly mediated through the inhibition of HDAC7.

Suberoylanilide hydroxamic acid (SAHA) causes tumor growth slowdown and triggers autophagy in glioblastoma stem cells

“…41,42 SAHA has also been shown to alleviate several neurological disorders. 43,44 In this study, our results showed that SAHA had specific effects on GSCs: SAHA specifically inhibits the growth of tumor sphere and triggered autophagy functions at the early phase.…”

Neuroprotection by Histone Deacetylase-7 (HDAC7) Occurs by Inhibition of c-jun Expression through a Deacetylase-independent Mechanism

“…But because the inhibitors used so far are not selective, the specific HDAC protein(s) that they inhibit in affording neuroprotection remain to be identified. A recent study examined the possibility that one target of these inhibitors is HDAC7 (17). Indeed, administration of HDAC inhibitors results in the down-regulation of HDAC7 expression in the brains of wild-type and R6/2 mice, a commonly used mouse model of Huntington disease (17).…”

“…Selective down-regulation of HDAC7 expression by another broad spectrum HDAC inhibitor, SAHA, has also been observed in a variety of normal, im-mortalized, genetically transformed, and human cancer-derived cell lines (17,18). Furthermore, administration of SAHA to mice results in the down-regulation of HDAC7 in the brain (17). These observations raise the possibility that elevated levels of HDAC7 are required for neuronal survival and that the neurotoxic effect of HDAC inhibitors on CGNs results from the reduction in HDAC7 expression.…”

“…Interestingly, the treatment of CGNs with either of two distinct HDAC inhibitors, TSA and MS-275, leads to reduced expression of HDAC7 and HDRP (7). Selective down-regulation of HDAC7 expression by another broad spectrum HDAC inhibitor, SAHA, has also been observed in a variety of normal, im-mortalized, genetically transformed, and human cancer-derived cell lines (17,18). Furthermore, administration of SAHA to mice results in the down-regulation of HDAC7 in the brain (17).…”

Synthetic zinc finger repressors reduce mutant huntingtin expression in the brain of R6/2 mice

“…R6/2 transgenic mice were purchased from the Jackson Laboratories [B6CBA-Tg(HDexon1)62Gpb/3J]. Ovarian-transplanted hemizygous females and wt B6CBAF1/J males were bred in-house, and progeny was genotyped as previously described (50). Animal handling procedures were conducted in accordance with Directive 86/609/EU of the European Commission and following protocols approved by the Ethical Committee of the Barcelona Biomedical Research Park.…”