Androgen Receptor SUMOylation in SBMA

描述（由申请人提供）：以蛋白质聚集为特征的神经退行性疾病包括9种由CAG/谷氨酰胺束扩张引起的无法治疗的疾病。这些多谷氨酰胺（polyQ）疾病之一，脊髓球性肌萎缩症（SBMA），是一种由雄激素受体（AR）基因突变引起的下运动神经元退行性疾病。突变蛋白经历激素依赖的核易位、展开和寡聚化，这些步骤对毒性和男性进行性肢体近端和球肌无力的发展至关重要。虽然这种致病突变在大约20年前就被发现了，但SBMA发病机制的核心机制仍然知之甚少，现有的治疗方法在很大程度上是支持的。最近的研究表明，配体引发的AR翻译后修饰影响毒性。我们的实验室已经证明，通过SUMO（小泛素样修饰剂）偶联多q AR会损害突变蛋白的配体依赖性寡聚化。然而，这种修饰在体内改变疾病表型的程度目前尚不清楚。本应用的目的是确定聚q AR的sumo化在多大程度上影响SBMA发病机制。我们的中心假设是聚q AR的sumo化降低了SBMA的神经肌肉毒性。这一假设源于我们自己的初步数据，表明SUMOylation降低了SBMA细胞模型中可溶性AR低聚物和聚集体的水平。在这里，我们将使用基因靶向产生表达SUMO抗性多q AR的敲入小鼠，以确定该途径影响疾病发病机制的程度。提出的工作的基本原理是，定义SUMOylation途径在疾病中的作用将产生对致病的见解

DESCRIPTION (provided by applicant): The neurodegenerative disorders characterized by protein aggregation include nine untreatable diseases caused by CAG/glutamine tract expansions. One of these polyglutamine (polyQ) diseases, spinobulbar muscular atrophy (SBMA), is a degenerative disorder of lower motor neurons caused by a mutation in the androgen receptor (AR) gene. The mutant protein undergoes hormone-dependent nuclear translocation, unfolding and oligomerization, steps that are critical to toxicity and to the development of progressive proximal limb and bulbar muscle weakness in men. Although the disease causing mutation was identified about two decades ago, mechanisms that are central to the pathogenesis of SBMA remain poorly understood and available therapies are largely supportive. Recent studies demonstrate that post-translational modifications of the AR triggered by ligand influence toxicity. Our laboratory has shown that conjugation of the polyQ AR by SUMO (small ubiquitin-like modifier) impairs ligand-dependent oligomerization of the mutant protein. However, the extent to which this modification alters the disease phenotype in vivo is currently unknown. The objective of this application is to determine the extent to which SUMOylation of the polyQ AR affects SBMA pathogenesis. Our central hypothesis is that SUMOylation of the polyQ AR diminishes neuromuscular toxicity in SBMA. This hypothesis springs from our own preliminary data demonstrating that SUMOylation decreases the levels of soluble AR oligomers and aggregates in cellular models of SBMA. Here we will use gene targeting to generate knock-in mice expressing a SUMO resistant polyQ AR to determine the extent to which this pathway affects disease pathogenesis. The rationale of the proposed work is that defining the role of the SUMOylation pathway in disease will yield insights into pathogenic mechanisms and accelerate the discovery of targets for disease- modifying therapies. Genetic and biochemical approaches will be combined with characterization of mouse behavioral and neuropathological changes to establish the effects of polyQ AR SUMOylation in a knock-in mouse model of SBMA. These studies are expected to have a significant positive impact by defining the role of SUMOylation in SBMA and thereby identifying potential therapeutic targets. As several neurodegenerative disease-causing proteins are targeted by SUMO, we anticipate that our findings will also serve as a paradigm for understanding the effects of SUMOylation on the phenotype of these related disorders.