The Role of the AR N/C Interaction in SMBA

描述(申请人提供)：许多神经退行性疾病，包括脊髓和延髓肌萎缩症(SBMA)和肌萎缩侧索硬化症(ALS)，都是由于各种遗传和环境原因导致的蛋白质错误折叠和堆积。SBMA是一种成人起病的神经肌肉疾病，由雄激素受体(AR)内的聚谷氨酰胺扩张引起；它与其他由聚谷氨酰胺扩张引起的神经退行性疾病在机制上有关。尽管导致神经元功能障碍和死亡的确切途径尚不清楚，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。我们的转基因细胞和SBMA小鼠模型复制了依赖多谷氨酰胺的蛋白分解和核聚集的邻近事件，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与其他聚谷氨酰胺疾病的不同之处在于它的发生和发展是雄激素依赖性的。我们在SBMA细胞模型中的初步研究表明，AR的结构变化发生在雄激素结合时，涉及氨基(N-)和羧基(C-)末端区域之间的域间相互作用，这是突变的AR聚集和毒性所必需的。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，并发展对这一作用的机制理解。我们预测，这些研究将揭示AR运输和代谢中被聚谷氨酰胺扩张破坏的一个或多个步骤的进一步细节。为了达到这些目标，我们提出了三个具体的目标：1)使用成像和生化方法评估聚谷氨酰胺扩张对AR N/C相互作用的影响；2)在SBMA小鼠模型中确定AR N/C相互作用的作用；3)确定N/C相互作用影响多谷氨酰胺扩张AR代谢的机制基础。我们期待这些研究的结果将使我们对SBMA的分子发病机制有一个新的理解，并促进我们对SBMA新疗法的开发。 公共卫生相关性：脊髓和球部肌肉萎缩症(SBMA)是9种多谷氨酰胺疾病之一，这些疾病本身属于以蛋白质错误折叠和堆积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)。我们已经在SBMA中发现了一个新的靶点，它涉及突变的雄激素受体蛋白的跨域(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，这样做将为治疗开发打开新的和强大的机会。

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.