Nuclear mechanisms of polyglutamine toxicity in SBMA

SBMA 中聚谷氨酰胺毒性的核机制

基本信息

批准号：
9288238
负责人：
DIANE E MERRY
金额：
$ 34.13万
依托单位：
THOMAS JEFFERSON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-07-01 至 2019-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9288238
关键词：
Acetylation Agar Gel Electrophoresis Alzheimer&apos s Disease Amyotrophic Lateral Sclerosis Androgen Receptor Androgens Behavioral Binding Biochemical Cell model Characteristics DNA Binding Data Development Disease Disease Progression Drug Targeting Event Family Genetic Genetic Transcription Half-Life Hormones Huntington Disease In Vitro Intervention Investigation Lead Length Lysine Manuscripts Mediating Metabolism Modification Molecular Molecular Conformation Motor Neurons Mus Mutation Nature Nervous system structure Neurodegenerative Disorders Neurons Nuclear Nuclear Inclusion Output Parkinson Disease Pathogenesis Pathogenicity Pathologic Pathology Pathway interactions Pharmacology Phosphorylation Play Positioning Attribute Post-Translational Protein Processing Proteins Publishing Receptor Aggregation Research Resistance Role Series Site Symptoms Testing Toxic effect Transgenic Mice Wild Type Mouse Work in vivo interest male mouse model mutant neurotoxicity new therapeutic target novel null mutation polyglutamine protein metabolism protein misfolding protein protein interaction public health relevance receptor spinal and bulbar muscular atrophy therapeutic development therapeutic target transcriptome

项目摘要

DESCRIPTION (provided by applicant): The nature of the nuclear events that transform the mutant androgen receptor (AR) into a toxic species have become a major focus of study in the field of spinal and bulbar muscular atrophy (SBMA) research following the discovery that the onset and progression of disease are hormone-dependent. It is unknown at what point in its metabolism the mutant AR becomes toxic to motor neurons, although work from our lab and others has begun to dissect the pathological pathway. We have recently determined that nuclear localization of the polyglutamine-expanded AR is essential, but not sufficient, for disease. Therefore, hormone-dependent nuclear metabolism of the mutant AR, including post-translational modification, protein-protein interactions and degradation are critical points of interest in determining the events that lead to its toxicity. One post- translational modification f interest is acetylation. Known AR acetylation sites are clustered in the KLKK motif located in the hinge region at positions 630/632/633. Our published studies have revealed that acetylation of these lysine residues is required for both the aggregation and toxicity of polyglutamine-expanded AR in cell models. We propose in this application to determine the role of AR acetylation at these sites in vivo, through the characterization of transgenic mice that express a polyglutamine-expanded AR that is incapable of acetylation at these sites. In addition, through a series of distinct but interconnected studies, we propose to determine the mechanistic basis for the role of AR acetylation in disease. We expect that the results from these studies will allow us to determine whether acetylation of the mutant AR represents a valid drug target for further therapeutic development in SBMA. Moreover, we expect our mechanistic studies to provide answers to central questions regarding the pathogenic mechanisms mediating neurotoxicity in SBMA.

描述（由适用提供）：将突变体雄激素受体（AR）转化为有毒物种的核事件的性质已成为脊柱和鳞茎肌肉萎缩（SBMA）研究的主要研究重点，因为发现疾病的发作和进展是疾病的发作和进展。尽管我们的实验室和其他人已经开始剖析病理途径，但突变体的代谢在什么时候就对运动神经元有毒是未知的。我们最近确定，聚谷氨酰胺膨胀的AR的核定位是必不可少的，但对疾病不足。因此，突变体AR的马依赖性核代谢，包括翻译后修饰，蛋白质 - 蛋白质相互作用和降解是确定导致其毒性事件的关键点。一种翻译后修饰F的兴趣是乙酰化。已知的AR乙酰化位点聚集在位于630/632/633位置的铰链区域的KLKK基序中。我们已发表的研究表明，这些赖氨酸残留物在细胞模型中的聚集和毒性需要对这些赖氨酸残留物进行乙酰化。我们在此应用中提出，通过表达在这些位点无法在这些位点无法乙酰化的多谷氨酸膨胀的AR的转基因小鼠的表征来确定AR乙酰化在体内的作用。此外，通过一系列不同但相互联系的研究，我们建议确定AR乙酰化在疾病中的作用的机械基础。我们预计这些研究的结果将使我们能够确定突变体AR的乙酰化是否代表了SBMA进一步治疗性发育的有效药物靶标。此外，我们预计我们的机械研究会为介导SBMA神经毒性的致病机制提供回答。