Androgen Receptor SUMOylation in SBMA

描述(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种无法治疗的疾病，由CAG/谷氨酰胺束扩张引起。多聚谷氨酰胺(PolyQ)病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，称为脊髓延髓肌萎缩症(SBMA)。突变的蛋白质经历激素依赖的核转位、展开和寡聚，这些步骤对毒性和男性进行性近端肢体和球肌肉无力的发展至关重要。尽管这种导致突变的疾病在大约20年前就被发现，但SBMA发病机制仍然知之甚少，现有的治疗方法在很大程度上也是支持性的。最近的研究表明，由配体触发的AR的翻译后修饰会影响毒性。我们的实验室已经证明，多聚Q AR与SUMO(小泛素样修饰物)的结合会削弱突变蛋白的配体依赖的寡聚。然而，这种修饰在多大程度上改变了体内的疾病表型目前尚不清楚。这项应用的目的是确定多聚Q AR的SUMO化对SBMA发病的影响程度。我们的中心假设是，多聚Q受体的SUMO化可以减少SBMA的神经肌肉毒性。这一假说源于我们自己的初步数据，表明SUMO化降低了SBMA细胞模型中可溶性AR寡聚体和聚集体的水平。在这里，我们将使用基因打靶来产生表达相扑抗性PolyQ AR的敲入小鼠，以确定这一途径影响疾病发病的程度。这项拟议工作的基本原理是，定义SUMO化途径在疾病中的作用将产生对致病因素的见解 并加速发现疾病修正疗法的靶标。遗传和生化方法将结合小鼠行为和神经病理变化的特征来建立多Q AR SUMO化在SBMA敲入小鼠模型中的作用。这些研究有望通过确定SUMO化在SBMA中的作用，从而确定潜在的治疗靶点，从而产生重大的积极影响。由于几种神经退行性疾病蛋白是相扑的靶点，我们预计我们的发现也将作为理解SUMO化对这些相关疾病表型的影响的范例。

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.