Abstract

The long term goal for this work is to determine the molecular basis of Huntington's disease (HD). The basis for this progressive neurological disorder is an expanded CAG repeat in the Huntington gene that codes for a long polyglutamine repeat (11, 28, 51, 63, 69). The work proposed in this competitive renewal extends work completed during the first 2 years of funding during which the PI made a mouse with a 90 unit CAG repeat in the murine HD homolog (Hdh (CAG) 90). Recent work has shown the presence of Neuronal intranuclear inclusions (NIIs). The PI will also make mice with modifications of Hdh (CAG) 90 designed to enhance access of the polyglutamine-containing portion of the mutant protein to the nucleus. The PI will assess the role these modifications play in the formation of NIIs and the possible role NIIs play in causing abnormalities.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
2R01NS034492-04
Application #
2689551
Study Section
Neurology C Study Section (NEUC)
Program Officer
Oliver, Eugene J
Project Start
1998-09-30
Project End
2002-07-31
Budget Start
1998-09-30
Budget End
1999-07-31
Support Year
4
Fiscal Year
1998
Total Cost
Indirect Cost

  Institution

Name
University of Alabama Birmingham
Department
Biochemistry
Type
Schools of Dentistry
DUNS #
004514360
City
Birmingham
State
AL
Country
United States
Zip Code
35294

  Publications

Tallaksen-Greene, S J; Crouse, A B; Hunter, J M et al. (2005) Neuronal intranuclear inclusions and neuropil aggregates in HdhCAG(150) knockin mice. Neuroscience 131:843-52
Dixon, Karen T; Cearley, Jamie A; Hunter, Jesse M et al. (2004) Mouse Huntington's disease homolog mRNA levels: variation and allele effects. Gene Expr 11:221-31
Jackson, Walker S; Tallaksen-Greene, Sara J; Albin, Roger L et al. (2003) Nucleocytoplasmic transport signals affect the age at onset of abnormalities in knock-in mice expressing polyglutamine within an ectopic protein context. Hum Mol Genet 12:1621-9
Lin, C H; Tallaksen-Greene, S; Chien, W M et al. (2001) Neurological abnormalities in a knock-in mouse model of Huntington's disease. Hum Mol Genet 10:137-44
Cearley, J A; Detloff, P J (2001) Efficient repetitive alteration of the mouse Huntington's disease gene by management of background in the tag and exchange gene targeting strategy. Transgenic Res 10:479-88
Ordway, J M; Cearley, J A; Detloff, P J (1999) CAG-polyglutamine-repeat mutations: independence from gene context. Philos Trans R Soc Lond B Biol Sci 354:1083-8
Ordway, J M; Tallaksen-Greene, S; Gutekunst, C A et al. (1997) Ectopically expressed CAG repeats cause intranuclear inclusions and a progressive late onset neurological phenotype in the mouse. Cell 91:753-63
Ordway, J M; Detloff, P J (1996) In vitro synthesis and cloning of long CAG repeats. Biotechniques 21:609-10, 612