Mouse Model and Interactors for Machado-Joseph Disease

马查多-约瑟夫病小鼠模型和相互作用器

• 批准号: 6657327
• 负责人: VERONICA COLOMER
• 金额: $ 40.88万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-30 至 2005-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6657327
• 关键词: brain metabolism; cerebellar ataxia /dyskinesia; disease /disorder model; genetically modified animals; homopeptide; human tissue; immunocytochemistry; intermolecular interaction; laboratory mouse; model design /development; mutant; nerve /myelin protein; protein metabolism; protein sequence; proteolysis; western blottings; yeast two hybrid system

DESCRIPTION (Adapted from applicant's abstract): 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.

描述（改编自申请人摘要）：Machado Joseph病（MJD），