The role of androgen receptor acetylation in the polyglutamine disease SBMA

描述(申请人提供)：在发现疾病的发生和发展是激素依赖的之后，将突变的雄激素受体(AR)转化为有毒物种的核事件的性质已经成为脊髓和延髓肌萎缩症(SBMA)研究领域的主要研究重点。目前尚不清楚突变的AR在代谢的什么时候会对运动神经元产生毒性，尽管我们实验室和其他实验室的工作已经开始剖析这一病理途径。我们最近确定，聚谷氨酰胺扩大的AR的核定位是必要的，但不足以导致疾病。因此，突变的AR的激素依赖的核代谢，包括翻译后修饰、蛋白质-蛋白质相互作用、降解和切割是确定导致其毒性的事件的关键。一个令人感兴趣的翻译后修饰是乙酰化。已知的AR乙酰化位点聚集在位于铰链区630/632/633位置的KLKK基序中。我们的初步研究表明，在细胞模型中，这些赖氨酸残基的乙酰化是聚谷氨酰胺扩展AR聚集和毒性所必需的。在这项应用中，我们建议通过建立表达多谷氨酰胺扩展的AR的转基因小鼠来确定在体内这些位置的AR乙酰化的作用，该转基因小鼠不能在这些位置进行乙酰化。通过这些转基因小鼠的运动功能特征以及神经病理和生化特征，我们将确定630/632/633位氨基酸的AR乙酰化是否为体内疾病特征所必需的。我们希望这些研究的结果将使我们能够确定突变AR的乙酰化是否代表了SBMA进一步治疗开发的有效药物靶点。 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中确定了一个涉及突变雄激素受体蛋白乙酰化的治疗靶点。这里提出的研究将确定这种修饰在SBMA小鼠模型中的作用；确认SBMA中乙酰化的作用将为治疗开发打开新的和强大的机会。

DESCRIPTION (provided by applicant): The nature of the nuclear events that transform the mutant androgen receptor (AR) into a toxic species have become a major focus of study in the field of spinal and bulbar muscular atrophy (SBMA) research following the discovery that the onset and progression of disease are hormone-dependent. It is unknown at what point in its metabolism the mutant AR becomes toxic to motor neurons, although work from our lab and others has begun to dissect the pathological pathway. We have recently determined that nuclear localization of the polyglutamine-expanded AR is essential, but not sufficient for disease. Therefore, hormone-dependent nuclear metabolism of the mutant AR, including post-translational modification, protein-protein interactions, degradation and cleavage are critical points of interest in determining the events that lead to its toxicity. One post-translational modification of interest is acetylation. Known AR acetylation sites are clustered in the KLKK motif located in the hinge region at positions 630/632/633. Our preliminary studies have revealed that acetylation of these lysine residues is required for both the aggregation and toxicity of polyglutamine-expanded AR in cell models. We propose in this application to determine the role of AR acetylation at these sites in vivo, through the creation of transgenic mice that express a polyglutamine-expanded AR that is incapable of acetylation at these sites. Through the characterization of motor function, as well as neuropathological and biochemical features in these transgenic mice, we will determine whether acetylation of the AR at amino acids 630/632/633 is required for disease features in vivo. We expect that the results from these studies will allow us to determine whether acetylation of the mutant AR represents a valid drug target for further therapeutic development in 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 therapeutic target in SBMA that involves the acetylation of the mutant androgen receptor protein. The studies proposed here will determine the role for this modification in a mouse model of SBMA; the validation of a role for acetylation in SBMA will open new and powerful opportunities for therapeutic development.