Huntington's disease (HD), an inherited neurodegenerative disorder that affects the lives of more than 100,000 people in the US, is caused by an unstable CAG repeat in the 4p16.3 HD gene that encodes a variable polyglutamine tract in huntingtin. This grant continues to have the goal of using targeted mutations in the mouse's HD gene homolog (Hdh) to delineate this intriguing disease-initiating mechanism and its earliest consequences in striatum, to provide assays for identifying factors that modify the earliest steps in the disease process. Our studies comprise three new Aims. In exploring huntingtin function in the HD-trigger mechanism we have found that huntingtin may associate with and regulate the function and histone 3 methyltransferase activity of Eed polycomb repressive complex (PRC2/3).
Aim 1 will test this hypothesis and determine whether the effects of lengthening the polyglutamine tract in huntingtin may implicate huntingtin activity in the HD trigger mechanism.
Aim 2 will identify the transcriptional regulators of the immediate early gene response in striatum to the HD CAG repeat that causes the majority of HD cases, including Nrf1/E2F senescence target genes. To identify factors that make striatal neurons so vulnerable to the effects of the HD-trigger, Aim 3 will test the hypothesis that conditional expression of mutant huntingtin only in medium sized spiny striatal neurons will be sufficient to elicit the early disease cascade, indicating that the processes that modify the disease process are intrinsic to these cells. These studies will yield valuable information and assays for identifying genes and compounds that may interfere with the HD-trigger mechanism and its early effects in the striatal neurons that are the weakest link in HD patients.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS032765-15
Application #
7800923
Study Section
Neural Degenerative Disorders and Glial Biology Study Section (NDGB)
Program Officer
Sutherland, Margaret L
Project Start
1994-05-01
Project End
2012-03-31
Budget Start
2010-04-01
Budget End
2011-03-31
Support Year
15
Fiscal Year
2010
Total Cost
$369,240
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
Labadorf, Adam; Hoss, Andrew G; Lagomarsino, Valentina et al. (2015) RNA Sequence Analysis of Human Huntington Disease Brain Reveals an Extensive Increase in Inflammatory and Developmental Gene Expression. PLoS One 10:e0143563
Carroll, Jeffrey B; Deik, Amy; Fossale, Elisa et al. (2015) HdhQ111 Mice Exhibit Tissue Specific Metabolite Profiles that Include Striatal Lipid Accumulation. PLoS One 10:e0134465
Ramos, Eliana Marisa; Gillis, Tammy; Mysore, Jayalakshmi S et al. (2015) Haplotype analysis of the 4p16.3 region in Portuguese families with Huntington's disease. Am J Med Genet B Neuropsychiatr Genet 168B:135-43
Ramos, Eliana Marisa; Kovalenko, Marina; Guide, Jolene R et al. (2015) Chromosome substitution strain assessment of a Huntington's disease modifier locus. Mamm Genome 26:119-30
Biagioli, Marta; Ferrari, Francesco; Mendenhall, Eric M et al. (2015) Htt CAG repeat expansion confers pleiotropic gains of mutant huntingtin function in chromatin regulation. Hum Mol Genet 24:2442-57
Ramos, Eliana Marisa; Gillis, Tammy; Mysore, Jayalakshmi S et al. (2015) Prevalence of Huntington's disease gene CAG trinucleotide repeat alleles in patients with bipolar disorder. Bipolar Disord 17:403-8
Galkina, Ekaterina I; Shin, Aram; Coser, Kathryn R et al. (2014) HD CAGnome: a search tool for huntingtin CAG repeat length-correlated genes. PLoS One 9:e95556
Hoss, Andrew G; Kartha, Vinay K; Dong, Xianjun et al. (2014) MicroRNAs located in the Hox gene clusters are implicated in huntington's disease pathogenesis. PLoS Genet 10:e1004188
Zhang, Bin; Gaiteri, Chris; Bodea, Liviu-Gabriel et al. (2013) Integrated systems approach identifies genetic nodes and networks in late-onset Alzheimer's disease. Cell 153:707-20
Ramos, Eliana Marisa; Latourelle, Jeanne C; Gillis, Tammy et al. (2013) Candidate glutamatergic and dopaminergic pathway gene variants do not influence Huntington's disease motor onset. Neurogenetics 14:173-9

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