The Role of the AR Interactome in SBMA

项目摘要： 几种神经退行性疾病，包括阿尔茨海默病，帕金森病，以及 多聚谷氨酰胺扩增疾病是由于遗传因素引起的蛋白质错误折叠和积累而导致的。 和/或环境原因。脊髓延髓肌萎缩症（SBMA）是一种成人发病，遗传性， 由雄激素受体（AR）内的多聚谷氨酰胺扩增引起的神经肌肉疾病; 它与多聚谷氨酰胺扩增引起的其他神经退行性疾病有关，包括 亨廷顿氏病和几种脊髓小脑共济失调。尽管通往 神经元功能障碍和死亡是未知的，评价转基因小鼠和细胞模型， 这些疾病已经产生了对疾病发病机理的机械见解。SBMA除了 其他多聚谷氨酰胺疾病，因为其发病和进展依赖于AR雄激素 配体。我们的SBMA细胞和小鼠模型再现了雄激素和多聚谷氨酰胺依赖的 在患者中观察到的核AR聚集，以及随之而来的毒性，使得这些模型 对于AR毒性中涉及的上游事件的机制基础的分析非常有用。我们 长期目标是使用这些模型来发展对 糖依赖性、多聚谷氨酰胺扩展的AR毒性。越来越多的证据表明 长polyQ束导致细胞功能障碍并最终导致细胞死亡，至少部分原因是 维持正常细胞功能的蛋白质-蛋白质相互作用失调。我们利用了一个 定量蛋白质组学方法，以确定AR蛋白相互作用网络的变化引起的 在细胞模型中进行polyQ扩增，并鉴定了几种可能参与 polyQ扩增的AR致病性。我们对其中一个已确定的相互作用因子USP 7的初步研究 （与polyQ-扩展的AR的优先相互作用物），揭示了USP 7在SBMA中的作用。我们提出 在此，1）在经验证的脊髓和肌肉组织中进行额外的相互作用组筛选， SBMA小鼠模型，2）研究鉴定的其他差异相互作用蛋白的作用 在我们的初步筛选中，和3）继续我们对USP 7在SBMA中的作用的机制研究。我们 预计这些研究的结果将使我们更深入地了解分子 本发明的目的在于揭示SBMA的发病机制，并且将产生适合于SBMA的治疗调节的新途径。

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.