Abstract

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.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS045283-09
Application #
8477309
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
2013-06-01
Budget End
2014-05-31
Support Year
9
Fiscal Year
2013
Total Cost
$316,514
Indirect Cost
$109,642

  Institution

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

  Publications

Song, Wan; Zsindely, Nóra; Faragó, Anikó et al. (2018) Systematic genetic interaction studies identify histone demethylase Utx as potential target for ameliorating Huntington's disease. Hum Mol Genet 27:649-666
Chongtham, Anjalika; Barbaro, Brett; Filip, Tomas et al. (2018) Nonmammalian Models of Huntington's Disease. Methods Mol Biol 1780:75-96
Arystarkhova, Elena; Sweadner, Kathleen J (2016) Functional Studies of Na(+),K(+)-ATPase Using Transfected Cell Cultures. Methods Mol Biol 1377:321-32
Sweadner, Kathleen J (2016) Colorimetric Assays of Na,K-ATPase. Methods Mol Biol 1377:89-104
Barbaro, Brett A; Lukacsovich, Tamas; Agrawal, Namita et al. (2015) Comparative study of naturally occurring huntingtin fragments in Drosophila points to exon 1 as the most pathogenic species in Huntington's disease. Hum Mol Genet 24:913-25
Ochaba, Joseph; Lukacsovich, Tamás; Csikos, George et al. (2014) Potential function for the Huntingtin protein as a scaffold for selective autophagy. Proc Natl Acad Sci U S A 111:16889-94
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
Steele, J W; Lachenmayer, M L; Ju, S et al. (2013) Latrepirdine improves cognition and arrests progression of neuropathology in an Alzheimer's mouse model. Mol Psychiatry 18:889-97
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
Song, Wan; Smith, Marianne R; Syed, Adeela et al. (2013) Morphometric analysis of Huntington's disease neurodegeneration in Drosophila. Methods Mol Biol 1017:41-57

Showing the most recent 10 out of 32 publications