Huntington's Disease (HD) is one of several neurodegenerative diseases that affect millions of Americans. Many of these diseases are associated with transcriptional dysregulation. In the case of Huntington's disease, the relevance of this dysregulation to pathology has been demonstrated in Drosophila and mouse models of HD. HD is caused by an expanded poly- glutamine sequence in the huntingtin protein and several studies suggest that a proximal event in HD is the disruption of chromatin remodeling activities by the expanded polyQ protein. Chromatin therapy with Histone DeACetylase (HDAC) inhibitors is currently one of the most promising strategies being developed for the treatment of Huntington's disease (HD). These and other studies suggest that a more comprehensive approach to chromatin therapy based strategies may prove to be more beneficial. In this proposal, we will conduct a comprehensive analysis of the therapeutic potential of various chromatin-remodeling activities in an HD setting. These studies will help elucidate the mechanisms by which mutant Huntington affects cellular transcription and whether the therapeutic interventions are restorative or compensatory. .

Public Health Relevance

Many neurodegenerative diseases are characterized by disruptions in gene expression. Chromatin refers to the complex of DNA and proteins that control gene production, and the structure of this complex is disrupted in Huntington's Disease and other neurodegenerative diseases. The goal of this project is to develop new therapies to restore chromatin disruptions to their pre-disease state for the treatment of Huntington's Disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS045283-08
Application #
8272672
Study Section
Neural Oxidative Metabolism and Death Study Section (NOMD)
Program Officer
Sutherland, Margaret L
Project Start
2002-12-01
Project End
2015-05-31
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
8
Fiscal Year
2012
Total Cost
$413,295
Indirect Cost
$143,168
Name
University of California Irvine
Department
Anatomy/Cell Biology
Type
Organized Research Units
DUNS #
046705849
City
Irvine
State
CA
Country
United States
Zip Code
92697
Smith, Marianne R; Syed, Adeela; Lukacsovich, Tamas et al. (2014) A potent and selective Sirtuin 1 inhibitor alleviates pathology in multiple animal and cell models of Huntington's disease. Hum Mol Genet 23:2995-3007
O'Rourke, Jacqueline Gire; Gareau, Jaclyn R; Ochaba, Joseph et al. (2013) SUMO-2 and PIAS1 modulate insoluble mutant huntingtin protein accumulation. Cell Rep 4:362-75
Vashishtha, Malini; Ng, Christopher W; Yildirim, Ferah et al. (2013) Targeting H3K4 trimethylation in Huntington disease. Proc Natl Acad Sci U S A 110:E3027-36
Bodai, Laszlo; Pallos, Judit; Thompson, Leslie Michels et al. (2012) Pcaf modulates polyglutamine pathology in a Drosophila model of Huntington's disease. Neurodegener Dis 9:104-6
Bodai, Laszlo; Marsh, J Lawrence (2012) A novel target for Huntington's disease: ERK at the crossroads of signaling. The ERK signaling pathway is implicated in Huntington's disease and its upregulation ameliorates pathology. Bioessays 34:142-8
Maher, Pamela; Dargusch, Richard; Bodai, Laszlo et al. (2011) ERK activation by the polyphenols fisetin and resveratrol provides neuroprotection in multiple models of Huntington's disease. Hum Mol Genet 20:261-70
Luthi-Carter, Ruth; Taylor, David M; Pallos, Judit et al. (2010) SIRT2 inhibition achieves neuroprotection by decreasing sterol biosynthesis. Proc Natl Acad Sci U S A 107:7927-32
McConoughey, Stephen J; Basso, Manuela; Niatsetskaya, Zoya V et al. (2010) Inhibition of transglutaminase 2 mitigates transcriptional dysregulation in models of Huntington disease. EMBO Mol Med 2:349-70
Ossato, Giulia; Digman, Michelle A; Aiken, Charity et al. (2010) A two-step path to inclusion formation of huntingtin peptides revealed by number and brightness analysis. Biophys J 98:3078-85
Gu, Xiaofeng; Greiner, Erin R; Mishra, Rakesh et al. (2009) Serines 13 and 16 are critical determinants of full-length human mutant huntingtin induced disease pathogenesis in HD mice. Neuron 64:828-40

Showing the most recent 10 out of 21 publications