Huntington's disease is a progressive neurodegenerative disease for which no effective treatment exists. Transcriptional dysregulation is now considered to be an important mechanism in the pathogenesis of Huntington's disease (HD) and other polyglutamine diseases. Alteration of mRNA populations, including those encoding for neurotransmitter receptors, is a hallmark of murine and cellular models of HD as well as human HD. Although numerous studies have confirmed that mRNA populations are altered in HD models, the mechanism underlying such changes remains unknown. Transcription factors, including specificity protein 1 (Sp1), have been implicated in HD pathogenesis, but the role of altered Sp1 function in producing mRNA alterations has not been answered. In this application, we take advantage of a well-described set of gene alterations--those occurring in neurotransmitter receptors--as a starting point for determining the molecular mechanisms of transcriptional dysregulation. We propose a series of hypotheses that will yield critical mechanistic insight into the processes that alter mRNA populations and cause disease pathogenesis.
Specific Aim 1 will test the hypothesis that mutant huntingtin selectively alters the association of Sp1 with the promoters of genes that are downregulated in HD. Chromatin Immunoprecipitation (CHIP) assays will assess the degree of Sp1-gene binding in cellular, murine and human HD tissues.
Specific Aim 2 will test the hypothesis that decreased Sp1 binding to selected gene promoters causes HD phenotypes. Sp1 levels will be manipulated through RNA interference, dominant negative constructs and overexpression, and the effects of these manipulations on mRNA and cellular toxicity will be assessed.
Specific Aim 3 tests the hypothesis that interference in Sp 1 function by huntingtin causes abnormal histone modification. Histone modifications will be examined in mouse and cell models of HD. Taken together, these proposed experiments will systematically address several key molecular loci of potential damage by mutant huntingtin. Such fundamental mechanistic information is critical to the eventual development of effective therapy for HD.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
2R01NS038106-05A2
Application #
6826505
Study Section
Special Emphasis Panel (ZRG1-CDIN (01))
Program Officer
Oliver, Eugene J
Project Start
1999-08-12
Project End
2009-04-30
Budget Start
2004-07-15
Budget End
2005-04-30
Support Year
5
Fiscal Year
2004
Total Cost
$363,179
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
McFarland, Karen N; Das, Sudeshna; Sun, Ting Ting et al. (2013) Genome-wide increase in histone H2A ubiquitylation in a mouse model of Huntington's disease. J Huntingtons Dis 2:263-77
McFarland, Karen N; Das, Sudeshna; Sun, Ting Ting et al. (2012) Genome-wide histone acetylation is altered in a transgenic mouse model of Huntington's disease. PLoS One 7:e41423
Benn, Caroline L; Luthi-Carter, Ruth; Kuhn, Alexandre et al. (2010) Environmental enrichment reduces neuronal intranuclear inclusion load but has no effect on messenger RNA expression in a mouse model of Huntington disease. J Neuropathol Exp Neurol 69:817-27
Kim, Mee-Ohk; Chawla, Prianka; Overland, Ryan P et al. (2008) Altered histone monoubiquitylation mediated by mutant huntingtin induces transcriptional dysregulation. J Neurosci 28:3947-57
Broom, Wendy J; Greenway, Matthew; Sadri-Vakili, Ghazaleh et al. (2008) 50bp deletion in the promoter for superoxide dismutase 1 (SOD1) reduces SOD1 expression in vitro and may correlate with increased age of onset of sporadic amyotrophic lateral sclerosis. Amyotroph Lateral Scler 9:229-37
Benn, Caroline L; Sun, Tingting; Sadri-Vakili, Ghazaleh et al. (2008) Huntingtin modulates transcription, occupies gene promoters in vivo, and binds directly to DNA in a polyglutamine-dependent manner. J Neurosci 28:10720-33
Cha, Jang-Ho J (2007) Transcriptional signatures in Huntington's disease. Prog Neurobiol 83:228-48
Benn, C L; Slow, E J; Farrell, L A et al. (2007) Glutamate receptor abnormalities in the YAC128 transgenic mouse model of Huntington's disease. Neuroscience 147:354-72
Cha, Jang-Ho J (2007) Finding diamonds in the rubble. Exp Neurol 205:1-4
Sadri-Vakili, Ghazaleh; Bouzou, Berengere; Benn, Caroline L et al. (2007) Histones associated with downregulated genes are hypo-acetylated in Huntington's disease models. Hum Mol Genet 16:1293-306

Showing the most recent 10 out of 27 publications