The Role of the AR N/C Interaction in SMBA

AR N/C 交互在 SMBA 中的作用

• 批准号: 8227179
• 负责人: DIANE E MERRY
• 金额: $ 33.91万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8227179
• 关键词: Adult; Alzheimer' s Disease; Amyotrophic Lateral Sclerosis; Androgen Receptor; Androgens; Animal Model; Behavior; Binding; Biochemical; C-terminal; Cell Nucleus; Cell model; Cessation of life; DNA Binding; Development; Disease; Evaluation; Event; Family; Fluorescence Resonance Energy Transfer; Genetic; Goals; Half-Life; Hormones; Huntington Disease; Image; Imaging Techniques; Intervention; Label; Lead; Metabolism; Modeling; Modification; Molecular; Molecular Conformation; Motor Neurons; Mutation; Neurodegenerative Disorders; Neuromuscular Diseases; Neuronal Dysfunction; Nuclear; Nuclear Export; PC12 Cells; Parkinson Disease; Pathogenesis; Pathology; Pathway interactions; Phosphorylation; Play; Post-Translational Protein Processing; Property; Proteolysis; Receptor Aggregation; Regulation; Role; Series; Symptoms; Techniques; Testing; Toxic effect; Transgenic Mice; Transgenic Organisms; Two-Hybrid System Techniques; Work; base; cofactor; improved; in vivo; mouse model; mutant; neuropathology; novel; novel therapeutics; polyglutamine; protein misfolding; receptor; research study; spinal and bulbar muscular atrophy; therapeutic development; therapeutic target; trafficking

DESCRIPTION (provided by applicant): Many neurodegenerative diseases, including spinal and bulbar muscular atrophy (SBMA) and ALS, result from protein misfolding and accumulation due to a variety of both genetic and environmental causes. SBMA is an adult-onset neuromuscular disease that is caused by polyglutamine expansion within the androgen receptor (AR); it is related mechanistically to other neurodegenerative diseases caused by polyglutamine expansion. Although the precise pathway leading to neuronal dysfunction and death is unknown, the evaluation of transgenic mouse and cell models of these diseases has yielded many mechanistic clues. Our transgenic cell and mouse models of SBMA reproduce the proximate events of polyglutamine-dependent proteolysis and nuclear aggregation, making these models highly useful for the analysis of the mechanistic basis for these upstream events. SBMA stands apart from other polyglutamine diseases in that its onset and progression are androgen- dependent. Our preliminary studies in cell models of SBMA indicate that a structural change in the AR that occurs upon androgen binding and that involves an interdomain interaction between the amino- (N-) and carboxyl- (C-) terminal regions is required for mutant AR aggregation and toxicity. Our long- term objectives are to use our transgenic mouse and cell models to determine the role of the N/C interaction in vivo and to develop a mechanistic understanding for this role. We predict that these studies will reveal further details about the step or steps in AR trafficking and metabolism that are derailed by the polyglutamine expansion. To reach these goals, we propose three specific aims: 1) To evaluate the effect of polyglutamine expansion on the AR N/C interaction, using both imaging and biochemical approaches; 2) To determine the role of the AR N/C interaction in a mouse model of SBMA; 3) To determine the mechanistic basis by which the N/C interaction impacts polyglutamine- expanded AR metabolism. We anticipate that results from these studies will lead us to a new understanding of the molecular pathogenesis of SBMA and enhance our development of new therapies for SBMA. PUBLIC HEALTH RELEVANCE: Spinal and bulbar muscular atrophy (SBMA) is one of 9 polyglutamine diseases, which are themselves part of a large family of neurodegenerative diseases characterized by protein misfolding and accumulation; these diseases also include Alzheimer's disease, Huntington's disease, Parkinson's disease and amyotrophic lateral sclerosis (ALS). We have identified a novel target in SBMA that involves the interdomain (N/C) interaction of the mutant androgen receptor protein. The studies proposed here will determine both the role and the mechanistic basis for this modification in SBMA, and in so doing, will open new and powerful opportunities for therapeutic development.

描述（由申请人提供）：许多神经退行性疾病，包括脊髓和延髓性肌萎缩症（SBMA）和 ALS，是由于各种遗传和环境原因导致的蛋白质错误折叠和积累造成的。 SBMA 是一种成人发病的神经肌肉疾病，由雄激素受体 (AR) 内的聚谷氨酰胺扩张引起；它在机制上与聚谷氨酰胺扩张引起的其他神经退行性疾病有关。尽管导致神经元功能障碍和死亡的精确途径尚不清楚，但对这些疾病的转基因小鼠和细胞模型的评估已经产生了许多机制线索。我们的 SBMA 转基因细胞和小鼠模型重现了多聚谷氨酰胺依赖性蛋白水解和核聚集的近期事件，使这些模型对于分析这些上游事件的机制基础非常有用。 SBMA 与其他多聚谷氨酰胺疾病的不同之处在于其发病和进展依赖于雄激素。我们对 SBMA 细胞模型的初步研究表明，雄激素结合时发生的 AR 结构变化，涉及氨基 (N-) 和羧基 (C-) 末端区域之间的域间相互作用，是突变 AR 聚集所必需的和毒性。我们的长期目标是使用我们的转基因小鼠和细胞模型来确定 N/C 相互作用在体内的作用，并建立对该作用的机制理解。我们预测这些研究将进一步揭示 AR 运输和代谢中因聚谷氨酰胺扩张而脱轨的一个或多个步骤的细节。为了实现这些目标，我们提出了三个具体目标：1）使用成像和生化方法评估聚谷氨酰胺扩增对 AR N/C 相互作用的影响； 2) 确定 AR N/C 相互作用在 SBMA 小鼠模型中的作用； 3)确定N/C相互作用影响聚谷氨酰胺扩展的AR代谢的机制基础。我们预计这些研究结果将使我们对 SBMA 的分子发病机制有新的认识，并促进我们对 SBMA 新疗法的开发。 公共卫生相关性：脊髓和延髓性肌萎缩症 (SBMA) 是 9 种多聚谷氨酰胺疾病之一，这些疾病本身属于以蛋白质错误折叠和积累为特征的神经退行性疾病大家族的一部分；这些疾病还包括阿尔茨海默病、亨廷顿病、帕金森病和肌萎缩侧索硬化症（ALS）。我们在 SBMA 中发现了一个新靶标，该靶标涉及突变型雄激素受体蛋白的域间 (N/C) 相互作用。这里提出的研究将确定 SBMA 中这种修饰的作用和机制基础，这样做将为治疗发展开辟新的强大机会。