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成为脊髓和球性肌萎缩症（SBMA）研究领域的主要研究焦点。目前尚不清楚突变AR在其代谢过程中的哪一点对运动神经元产生毒性，尽管我们的实验室和其他实验室已经开始剖析其病理途径。我们最近确定，聚谷氨酰胺扩增AR的核定位是必要的，但对疾病来说还不够。因此，突变体AR的激素依赖核代谢，包括翻译后修饰、蛋白-蛋白相互作用、降解和裂解，是确定导致其毒性事件的关键点。我们感兴趣的一种翻译后修饰是乙酰化。已知的AR乙酰化位点聚集在KLKK基序中，位于铰链区域的630/632/633位置。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增AR的聚集和毒性所必需的。我们建议在此申请中，通过创建转基因小鼠，表达在这些位点不能乙酰化的聚谷氨酰胺扩增AR，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和生化特征的表征，我们将确定体内疾病特征是否需要在氨基酸630/632/633处乙酰化AR。我们期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。

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.