Nuclear mechanisms of polyglutamine toxicity in 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AR是必不可少的，但不足以，疾病。因此，突变体AR依赖于蛋白质的核代谢，包括翻译后修饰、蛋白质-蛋白质相互作用和降解，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。我们已发表的研究表明，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。我们在本申请中提出，通过表征表达不能在这些位点乙酰化的多聚谷氨酰胺扩增的AR的转基因小鼠，来确定AR乙酰化在体内这些位点的作用。此外，通过一系列不同但相互关联的研究，我们建议确定AR乙酰化在疾病中作用的机制基础。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。此外，我们希望我们的机制研究提供答案的核心问题，介导SBMA神经毒性的致病机制。

 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 and degradation are critical points of interest in determining the events that lead to its toxicity. One post- translational modification f interest is acetylation. Known AR acetylation sites are clustered in the KLKK motif located in the hinge region at positions 630/632/633. Our published 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 characterization of transgenic mice that express a polyglutamine-expanded AR that is incapable of acetylation at these sites. In addition, through a series of distinct but interconnected studies, we propose to determine the mechanistic basis for the role of AR acetylation in disease. 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. Moreover, we expect our mechanistic studies to provide answers to central questions regarding the pathogenic mechanisms mediating neurotoxicity in SBMA.