Recently Huntington's disease (HD) and other triplet repeat disorders were found to be caused by expansions in the length of CAG codon repeat stretches in the mutated genes and mice transgenic for these mutations were created. The deleterious, biochemical consequences of this type of mutation remain unknown. Any clues to the biochemical effects of the mutation may, therefore, be vital clues to the toxic consequences of the mutation. We have found striking changes in dopamine D1 and D2, adenosine A2a and metabotropic glutamate type 2 receptor mRNA expression in three strains of mice transgenic for exon 1 of the HD gene with increased polyglutamines. The observed changes in receptor mRNA suggest that the truncated HD protein alters gene transcription. Few other biochemical changes have been found in HD transgenic mice. As such, it is one of the very few clues we can use to determine the pathologic mechanism of the disease. While receptor changes may themselves not cause disease, our data strongly suggest that receptor changes reflect a crucial, deleterious process which may include dysregulation of gene expression. Further, the magnitude of the change we have found (up to 90% decrease in presymptomatic mice) provides a strong readout that can be used in mechanistic and therapeutic studies. We will determine the generalizability and validity of these changes by measuring the levels of mRNA and protein expression for these receptors and control receptors in identified neuronal types of cortex, striatum, hippocampus and cerebellum in HD transgenic and littermate control mice as well as post-mortem presymptomatic HD and control human brains using techniques we have developed over the last 15 years; double label isotopic and nonisotopic in situ hybridization, immunoblotting, ligand binding assays and immuno-cytochemistry. We also will determine the relationship of the changes to the development of the neuronal intranuclear inclusions. (NII) that have been seen in both these mice and in human HD, whether they occur in cultured cells transfected with the mutant HD gene and the degree to which receptor changes correlate with CAG repeat number in human, mouse and cultured cells.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS038106-04
Application #
6529239
Study Section
Special Emphasis Panel (ZRG1-BDCN-2 (01))
Program Officer
Oliver, Eugene J
Project Start
1999-08-12
Project End
2003-07-31
Budget Start
2002-08-01
Budget End
2003-07-31
Support Year
4
Fiscal Year
2002
Total Cost
$444,026
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02199
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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
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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

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