The Role of the AR Interactome in SBMA

项目总结： 几种神经退行性疾病，包括阿尔茨海默氏症，帕金森氏症，以及 聚谷氨酰胺扩张性疾病，是由于遗传导致的蛋白质错误折叠和积聚 和/或环境原因。脊髓和延髓肌萎缩症(SBMA)是一种成人起病的遗传性疾病。 由雄激素受体(AR)内的多聚谷氨酰胺膨胀引起的神经肌肉疾病； 它与聚谷氨酰胺扩张引起的其他神经退行性疾病有关，包括 亨廷顿氏病和几个脊髓小脑性共济失调。尽管通向地球的准确路径 神经元功能障碍和死亡尚不清楚，转基因小鼠和细胞模型的评估 这些疾病已经对疾病的发病机制产生了机械性的见解。SBMA与 其他多谷氨酰胺疾病，其发生和发展依赖于AR雄激素 配基。我们的细胞和小鼠SBMA模型复制了雄激素和多谷氨酰胺依赖的 在患者中看到的核AR聚集以及由此产生的毒性，使这些模型 对于分析与AR毒性有关的上游事件的机理基础非常有用。我们的 长期目标是使用这些模型来发展对 激素依赖，多聚谷氨酰胺扩大的AR毒性。越来越多的证据表明 这种长的多聚Q链会导致细胞功能障碍，最终导致细胞死亡，至少部分是通过 维持正常细胞功能的蛋白质-蛋白质相互作用失调。我们已经利用了一个 应用定量蛋白质组学方法鉴定急性呼吸窘迫综合征引起的AR蛋白相互作用网络的变化 细胞模型中的多聚Q扩展，并确定了几个可能参与的候选蛋白质 多聚Q-扩展的AR致病力。我们对已确定的相互作用子USP7的初步研究 (一种具有多Q扩展AR的优先交互作用)，揭示了USP7在SBMA中的作用。我们建议 在这里1)在脊髓和肌肉组织中进行额外的交互作用组筛查 小鼠SBMA模型，2)研究其他差异相互作用蛋白的作用 在我们的初始筛选中，以及3)继续我们对USP7在SBMA中作用的机制研究。我们 预计这些研究的结果将使我们对分子有更深的了解。 SBMA的发病机制，并将为SBMA的治疗调控提供新的途径。

Project Summary: Several neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, as well as the polyglutamine expansion diseases, result from protein misfolding and accumulation due to genetic and/or environmental causes. Spinal and bulbar muscular atrophy (SBMA) is an adult-onset, inherited neuromuscular disease that is caused by polyglutamine expansion within the androgen receptor (AR); it is related to other neurodegenerative diseases caused by polyglutamine expansion, including Huntington's disease and several spinocerebellar ataxias. Although the precise pathways leading to neuronal dysfunction and death are unknown, the evaluation of transgenic mouse and cell models of these diseases has yielded mechanistic insights into disease pathogenesis. SBMA stands apart from other polyglutamine diseases in that its onset and progression are dependent on AR androgenic ligands. Our cell and mouse models of SBMA reproduce the androgen- and polyglutamine-dependent nuclear AR aggregation seen in patients, as well as its consequent toxicity, making these models highly useful for the analysis of the mechanistic basis for upstream events involved in AR toxicity. Our long-term objectives are to use these models to develop a mechanistic understanding of hormone-dependent, polyglutamine-expanded AR toxicity. A growing body of evidence suggests that long polyQ tracts cause cellular dysfunction and ultimately cell death, at least in part by dysregulating protein-protein interactions that sustain normal cellular function. We have utilized a quantitative proteomics approach to identify changes in the AR protein interaction network caused by polyQ expansion in a cell model, and identified several protein candidates that may be involved in polyQ-expanded AR pathogenicity. Our preliminary studies on one of the identified interactors, USP7 (a preferential interactor with polyQ-expanded AR), reveals a role for USP7 in SBMA. We propose here to 1) carry out additional interactome screens in spinal cord and muscle tissues of a validated mouse model of SBMA, 2) investigate the roles of the other differentially interacting proteins identified in our initial screen, and 3) continue our mechanistic studies of the role of USP7 in SBMA. We anticipate that results from these studies will lead us to a deeper understanding of the molecular pathogenesis of SBMA, and will yield novel pathways amenable to therapeutic modulation for SBMA.