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.
Highlights
Huntington’s disease (HD) is a progressive neurological disorder for which there is no effective disease-modifying treatment [1,2]
HDAC4 protein levels were measured in three different brain regions: cortex, hippocampus and brain stem (Fig. 1) by SDS-PAGE and immunoblotting with an N-terminal anti-HDAC4 antibody (Sigma) as well as with an HDAC4 antibody that had been raised against a peptide adjacent to the deacetylase domain (Santa Cruz)
We observed a significant reduction in HDAC4 in the cortex and brain stem but not in the hippocampus of both WT (Fig. 1A) and R6/2 (Fig. 1B) mice treated with Suberoylanilide hydroxamic acid (SAHA) as compared to vehicle
Summary
Huntington’s disease (HD) is a progressive neurological disorder for which there is no effective disease-modifying treatment [1,2]. The disease is caused by the expansion of a CAG repeat to more than 35 CAGs within exon 1 of the HTT gene. This leads to a wide-range of characteristic symptoms including personality changes, motor impairment and weight loss, which progress over the course of 15–20 years to death [3]. Transcription is regulated at the level of chromatin by a variety of epigenetic marks. This includes the covalent modification of conserved lysine residues within histone proteins and is orchestrated by histone acetylases (HATs) and histone deacetylases (HDACs). Much effort has been directed towards developing HDAC inhibitors as an HD therapeutic [17] and initial genetic studies performed in flies and worms have confirmed that these may have a significant potential [14,18,19]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
