Nuclear mechanisms of polyglutamine toxicity in SBMA

SBMA 中聚谷氨酰胺毒性的核机制

• 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
• 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' 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

 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(申请人提供)：在发现疾病的发生和发展是激素依赖的之后，将突变的雄激素受体(AR)转化为有毒物种的核事件的性质已经成为脊髓和延髓肌萎缩症(SBMA)研究领域的主要研究重点。目前尚不清楚突变的AR在代谢的什么时候会对运动神经元产生毒性，尽管我们实验室和其他实验室的工作已经开始剖析这一病理途径。我们最近已经确定，聚谷氨酰胺扩大的AR的核定位对于疾病是必要的，但不是充分的。因此，突变体AR的激素依赖性核代谢，包括翻译后修饰、蛋白质-蛋白质相互作用和降解，是确定导致其毒性的事件的关键。一个令人感兴趣的翻译后修饰是乙酰化。已知的AR乙酰化位点聚集在位于铰链区630/632/633位置的KLKK基序中。我们已发表的研究表明，在细胞模型中，这些赖氨酸残基的乙酰化是聚谷氨酰胺扩展AR聚集和毒性所必需的。在这项应用中，我们建议通过对表达多谷氨酰胺扩展的AR的转基因小鼠的鉴定，确定AR乙酰化在体内这些位置的作用，这些AR不能在这些位置乙酰化。此外，通过一系列不同但相互关联的研究，我们建议确定AR乙酰化在疾病中作用的机制基础。我们希望这些研究的结果将使我们能够确定突变AR的乙酰化是否代表了SBMA进一步治疗开发的有效药物靶点。此外，我们希望我们的机制研究能够为有关SBMA神经毒性的致病机制的核心问题提供答案。