The Role of the AR N/C Interaction in SMBA

描述（由申请人提供）：许多神经退行性疾病，包括脊髓和球性肌萎缩症（SBMA）和ALS，是由各种遗传和环境原因引起的蛋白质错误折叠和积累引起的。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；它与聚谷氨酰胺扩张引起的其他神经退行性疾病有机制关系。虽然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提供了许多机制线索。我们的转基因细胞和小鼠SBMA模型再现了聚谷氨酰胺依赖性蛋白水解和核聚集的近似事件，使这些模型对分析这些上游事件的机制基础非常有用。SBMA与其他多谷氨酰胺疾病不同，它的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，突变AR聚集和毒性需要发生在雄激素结合时的AR结构变化，并且涉及氨基（N-）和羧基（C-）末端区域之间的结构域间相互作用。我们的长期目标是利用我们的转基因小鼠和细胞模型来确定体内N/C相互作用的作用，并对这一作用的机制进行理解。我们预测，这些研究将揭示更多关于AR运输和代谢的细节，这些细节是由多聚谷氨酰胺扩增引起的。为了实现这些目标，我们提出了三个具体目标：1)利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相互作用在小鼠SBMA模型中的作用；3)确定N/C相互作用影响聚谷氨酰胺扩展AR代谢的机制基础。我们期待这些研究结果将引导我们对SBMA的分子发病机制有新的认识，并促进SBMA新疗法的开发。

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.