The Department of Molecular and Cell Biology would like to welcome Dr. Elizabeth Thomas, Associate Professor, Department of Molecular and Cell Biology, from The Scripps Research Institute to the campus. Dr. Thomas will be presenting, "Selective Histone Deacetylase (HDAC) Inhibitors asTherapeutics for Neurological Diseases". There will be a Reception at 3:45 p.m. FO 3.606.
Histone deacetylases (HDACs) enzymes, which affect the acetylation status of histones and other important cellular proteins, have been recognized as potentially useful therapeutic targets for a broad range of human disorders. An important question for HDAC inhibitor therapeutics is which HDAC enzyme(s) is/are important for disease phenotype amelioration, as it has become clear that individual HDAC enzymes play different biological roles in the brain. We have investigated a panel of novel benzamide-type HDAC inhibitors showing different selectivity profiles against class I HDACs for their ability to ameliorate huntingtin-elicited phenotypes in fly, cell and mouse models of Huntington’s disease (HD). Our findings demonstrate that HDAC1- and HDAC3-targetting compounds are most effective in ameliorating neurodegeneration in HD flies and metabolic deficits in mutant striatal cells, with HDAC3-selective compounds exhibiting some of the most potent effects.
Similarly, we find that HDAC3-targetting compounds improve behavioral symptoms in different HD mouse models, and in mouse models of other neurological diseases. We are investigating potential molecular mechanisms of action of HDAC inhibitors, by exploring the effects of HDAC inhibition on gene expression profiles. Results from these studies have indicated that HDAC1/3-targeting HDAC inhibitors act to modify the ubiquitin–proteasome and autophagy systems, which results in the degradation/clearance of important disease proteins. Further, our findings implicate HDAC inhibition in mechanisms of DNA methylation, which will be discussed. Overall, our findings suggest that HDAC inhibitors targeting HDACs1 and 3 would show therapeutic benefit for HD, as well as other human CNS disorders.