The role of androgen receptor acetylation in the polyglutamine disease SBMA

描述（由申请人提供）：在发现疾病的发作和进展具有神经依赖性之后，将突变雄激素受体（AR）转化为毒性物质的核事件的性质已成为脊髓延髓肌萎缩症（SBMA）研究领域的主要研究焦点。目前尚不清楚突变体AR在其代谢过程中的什么时候对运动神经元产生毒性，尽管我们实验室和其他人的工作已经开始剖析病理途径。我们最近已经确定，核定位的多聚谷氨酰胺扩展的AR是必不可少的，但不足以疾病。因此，突变体AR的依赖于细胞核的代谢，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点。一种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位的KLKK基序中。我们的初步研究表明，这些赖氨酸残基的乙酰化是细胞模型中聚谷氨酰胺扩增AR的聚集和毒性所必需的。在本申请中，我们提出通过产生表达不能在这些位点乙酰化的聚谷氨酰胺扩增的AR的转基因小鼠来确定AR乙酰化在体内这些位点的作用。通过对这些转基因小鼠的运动功能以及神经病理学和生化特征的表征，我们将确定体内疾病特征是否需要氨基酸630/632/633处的AR乙酰化。我们期望这些研究的结果将使我们能够确定突变体AR的乙酰化是否代表SBMA进一步治疗开发的有效药物靶标。 公共卫生相关性：脊髓延髓肌萎缩症（SBMA）是9种多聚谷氨酰胺疾病之一，其本身是以蛋白质错误折叠和积累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）。我们已经确定了SBMA的治疗靶点，涉及突变雄激素受体蛋白的乙酰化。这里提出的研究将确定这种修饰在SBMA小鼠模型中的作用;乙酰化在SBMA中的作用的验证将为治疗开发开辟新的强大的机会。

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.