Modulation of ataxin-1 phosphorylation

ataxin-1 磷酸化的调节

• 批准号: 6986197
• 负责人: Harry T. Orr
• 金额: $ 16.37万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-12-01 至 2006-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6986197
• 关键词: alanine; bioassay; cerebellar ataxia /dyskinesia; combinatorial chemistry; drug screening /evaluation; gene mutation; nerve /myelin protein; nuclear proteins; nucleic acid repetitive sequence; phosphorylation; protein localization; protein structure function; serine; tissue /cell culture

DESCRIPTION (provided by applicant): Spinocerebeltar ataxia type 1 (SCA1) is an autosomal dominant neurodegenerative disorder caused by the expansion of a glutamine repeat within the SCAl-encoded protein ataxin-l. The subcellular localization and deposition of mutant ataxin-1 is a critical factor in the pathogenesis of SCA1. The mechanism(s) that control these events are not understood, however, phosphorylation is a mean to control protein localization and degradation. We sought to determine if ataxin-1 is phosphorylated, and have shown that serine 776 (S776) of both wild type and mutant ataxin-1 is phosphorylated in vivo and in vitro. Preventing phosphorylation of this residue by replacing it with alanine results in a mutant protein found in the nucleus that is not pathogenic. The goal of the research described below is to develop a cell culture based assay that can be used to screen a compound library for modulators of ataxin-1 serine 776 phosphorylation. Such a screen will identify new molecular tools to aid in elucidating the mechanism of SCA1 pathogenesis. Moreover, identified compounds will provide potential leads toward the development of a therapeutic treatment for SCA1. Lead compounds that have been validated will be used to begin preclinical testing using a mouse model of SCA1.

描述（由申请人提供）：