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.
| Colomer Gould, Veronica F; Goti, Daniel; Pearce, Donna et al. (2007) A mutant ataxin-3 fragment results from processing at a site N-terminal to amino acid 190 in brain of Machado-Joseph disease-like transgenic mice. Neurobiol Dis 27:362-9 |
| Colomer Gould, V F; Goti, D; Kiluk, J (2006) A neuroendocrine dysfunction, not testicular mutant ataxin-3 cleavage fragment or aggregate, causes cell death in testes of transgenic mice. Cell Death Differ 13:524-6 |
| Goti, Daniel; Katzen, Scott M; Mez, Jesse et al. (2004) A mutant ataxin-3 putative-cleavage fragment in brains of Machado-Joseph disease patients and transgenic mice is cytotoxic above a critical concentration. J Neurosci 24:10266-79 |
