Display Settings:

Format

Send to:

Choose Destination
See comment in PubMed Commons below
PLoS Curr. 2010 Sep 2;2. pii: RRN1172. doi: 10.1371/currents.RRN1172.

Evaluation of histone deacetylases as drug targets in Huntington's disease models. Study of HDACs in brain tissues from R6/2 and CAG140 knock-in HD mouse models and human patients and in a neuronal HD cell model.

Author information

  • 1MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, & Harvard Medical School, Bldg. 114-3300, 16th Street, Charlestown, MA 02129, USA.

Abstract

The family of histone deacetylases (HDACs) has recently emerged as important drug targets for treatment of slow progressive neurodegenerative disorders, including Huntington's disease (HD). Broad pharmaceutical inhibition of HDACs has shown neuroprotective effects in various HD models. Here we examined the susceptibility of HDAC targets for drug treatment in affected brain areas during HD progression. We observed increased HDAC1 and decreased HDAC4, 5 and 6 levels, correlating with disease progression, in cortices and striata of HD R6/2 mice. However, there were no significant changes in HDAC protein levels, assessed in an age-dependent manner, in HD knock-in CAG140 mice and we did not observe significant changes in HDAC1 levels in human HD brains. We further assessed acetylation levels of α-tubulin, as a biomarker of HDAC6 activity, and found it unchanged in cortices from R6/2, knock-in, and human subjects at all disease stages. Inhibition of deacetylase activities was identical in cortical extracts from R6/2 and wild-type mice treated with a class II-selective HDAC inhibitor. Lastly, treatment with class I- and II-selective HDAC inhibitors showed similar responses in HD and wild-type rat striatal cells. In conclusion, our results show that class I and class II HDAC targets are present and accessible for chronic drug treatment during HD progression and provide impetus for therapeutic development of brain-permeable class- or isoform-selective inhibitors.

PMID:
20877454
[PubMed]
PMCID:
PMC2943247
Free PMC Article

Images from this publication.See all images (8)Free text

Figure 1.
Figure 2. Levels of class I HDAC proteins in cortex of CAG140 knock-in mice and HD patients.
Figure 3
Figure 4. Levels of class II HDAC4, HDAC5, HDAC6 proteins in cortex of CAG140 HD knock-in mice. A
Figure 5
Figure
Figure 7
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Icon for Public Library of Science Icon for PubMed Central
    Loading ...
    Write to the Help Desk