Huntington's disease (HD) is a devastating fatal neurodegenerative disorder caused by the expansion of a polymorphic CAG repeat in the HD gene that triggers cell death with a specificity towards neurons in the striatum and cortex. Although the underlying genetic mutation was discovered over 15 years ago, there is still no cure or effective treatment despite extensive efforts to understand the molecular pathways that lead to neurodegeneration. In recent years it has become apparent that the HD CAG repeat mutation undergoes dramatic tissue-specific somatic expansion, particularly in the brain regions affected in the disorder. This raises the hypothesis that somatic HD CAG length increases in target tissues contribute to HD pathogenesis. Data that we have generated during the past funding cycle both in accurate genetic Hdh CAG knock-in mouse models of HD and in postmortem brain from HD individuals strongly support this hypothesis, implying that factors that modify somatic instability may also be modifiers of disease. Here we propose experiments to elucidate further a) the factors that contribute to somatic instability and HD pathogenesis, and b) the relationship of somatic instability to disease phenotypes.
In Aim 1 we will identify and characterize the genetic variants that underlie the difference in somatic instability and the difference in an early phenotype between congenic Hdh CAG knock-in mouse strains on two inbred genetic backgrounds.
In Aim 2 we will cross Hdh CAG knock-in mice onto a mouse background (Msh3-/-) that displays no somatic instability and determine the effect on behavioral phenotypes and late-stage pathology.
In Aim 3 we will quantify somatic instability in a large collection of HD postmortem brains and perform a genome-wide association study for modifiers of somatic instability in HD patients. We will also investigate instability in neurons derived from induced pluripotent stem (iPS) cells from HD patients with the aim of generating a cell culture model of instability as an alternative to screen for modifiers of instability in humans. Together, these studies will provide insight into the factors that contribute to somatic instability and the HD pathogenic process. This will lead to novel therapeutic targets both for HD and other trinucleotide repeat diseases based upon a strategy of attacking the DNA mutation itself.

Public Health Relevance

Huntington's disease is a devastating, fatal neurodegenerative disorder for which there is no cure or effective treatment. The combination of emotional, cognitive and motor symptoms, leading to long-term care needs results in an extremely high healthcare cost, estimated at 25 billion dollars a year. This study is aimed at identifying early modifiers of disease with the potential of discovering novel targets for early therapeutic intervention.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS049206-08
Application #
8244952
Study Section
Molecular Neurogenetics Study Section (MNG)
Program Officer
Sutherland, Margaret L
Project Start
2004-07-01
Project End
2015-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
8
Fiscal Year
2012
Total Cost
$371,557
Indirect Cost
$157,182
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
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
Pinto, Ricardo Mouro; Dragileva, Ella; Kirby, Andrew et al. (2013) Mismatch repair genes Mlh1 and Mlh3 modify CAG instability in Huntington's disease mice: genome-wide and candidate approaches. PLoS Genet 9:e1003930
Hölter, Sabine M; Stromberg, Mary; Kovalenko, Marina et al. (2013) A broad phenotypic screen identifies novel phenotypes driven by a single mutant allele in Huntington's disease CAG knock-in mice. PLoS One 8:e80923
Lee, Jong-Min; Galkina, Ekaterina I; Levantovsky, Rachel M et al. (2013) Dominant effects of the Huntington's disease HTT CAG repeat length are captured in gene-expression data sets by a continuous analysis mathematical modeling strategy. Hum Mol Genet 22:3227-38
Staropoli, John F; Haliw, Larissa; Biswas, Sunita et al. (2012) Large-scale phenotyping of an accurate genetic mouse model of JNCL identifies novel early pathology outside the central nervous system. PLoS One 7:e38310
Mochel, Fanny; Durant, Brandon; Meng, Xingli et al. (2012) Early alterations of brain cellular energy homeostasis in Huntington disease models. J Biol Chem 287:1361-70
Kovalenko, Marina; Dragileva, Ella; St Claire, Jason et al. (2012) Msh2 acts in medium-spiny striatal neurons as an enhancer of CAG instability and mutant huntingtin phenotypes in Huntington's disease knock-in mice. PLoS One 7:e44273
Fossale, Elisa; Seong, Ihn Sik; Coser, Kathryn R et al. (2011) Differential effects of the Huntington's disease CAG mutation in striatum and cerebellum are quantitative not qualitative. Hum Mol Genet 20:4258-67
Lee, Jong-Min; Pinto, Ricardo Mouro; Gillis, Tammy et al. (2011) Quantification of age-dependent somatic CAG repeat instability in Hdh CAG knock-in mice reveals different expansion dynamics in striatum and liver. PLoS One 6:e23647
Seong, Ihn Sik; Woda, Juliana M; Song, Ji-Joon et al. (2010) Huntingtin facilitates polycomb repressive complex 2. Hum Mol Genet 19:573-83

Showing the most recent 10 out of 17 publications