Machado Joseph disease (MJD), or spinocerebellar ataxia-3 (SCA-3), is the most common dominant spinocerebellar ataxia. MJD/SCA-3 is hereditary, neurodegenerative, and caused by glutamine expansion in the protein ataxin-3 (mutant ataxin-3) possibly resulting in a gain of function. The applicant's aim is to understand the mechanism(s) of neurodegeneration in MJD/SCA-3.
SPECIFIC Aim #1 : To facilitate the study MJD/SCA-3, the investigator will develop a mouse model. Transgenic mice were generated expressing human full-length mutant ataxin-3. The investigator will define the time course of behavior abnormalities and age at death. There will be a search for evidence of neurodegeneration.
SPECIFIC Aim #2 : The investigator will test the hypothesis that neurodegeneration is caused by a proteolytic event forming a toxic fragment. A small form of mutant ataxin-3 in transgenic mouse brain was identified. Its brain distribution will be determined. The putative cleavage site will be identified. The investigator will study transgenic mice expressing mutant ataxin-3 with the putative cleavage site mutated.
SPECIFIC Aim #3 : The applicant's aim is to test the hypothesis that mutant ataxin-3 interactors cause neurodegeneration. A mutant ataxin-3 interactor using the yeast-two-hybrid method was identified. The investigator will determine if the interaction occurs in mammalian cells and search/characterize for new interactors.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS042731-01
Application #
6419061
Study Section
Special Emphasis Panel (ZRG1-BDCN-3 (01))
Program Officer
Gwinn, Katrina
Project Start
2001-09-30
Project End
2005-08-31
Budget Start
2001-09-30
Budget End
2002-08-31
Support Year
1
Fiscal Year
2001
Total Cost
$367,875
Indirect Cost
Name
Johns Hopkins University
Department
Psychiatry
Type
Schools of Medicine
DUNS #
045911138
City
Baltimore
State
MD
Country
United States
Zip Code
21218