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。这些多聚谷氨酰胺（polyQ）疾病之一，脊髓延髓肌萎缩症（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。该突变蛋白经历了依赖于细胞核转位、解折叠和寡聚化，这些步骤对毒性和男性进行性近端肢体和延髓肌无力的发展至关重要。虽然致病突变是在大约二十年前发现的，但SBMA发病机制的核心仍然知之甚少，现有的治疗方法在很大程度上是支持性的。最近的研究表明，由配体触发的AR的翻译后修饰影响毒性。我们的实验室已经表明，通过SUMO（小泛素样修饰剂）缀合polyQ 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。本申请的目的是确定polyQ AR的SUMO化影响SBMA发病机制的程度。我们的中心假设是polyQ AR的SUMO化减少了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，我们将使用基因靶向来产生表达SUMO抗性polyQ AR的敲入小鼠，以确定该途径影响疾病发病机制的程度。这项工作的基本原理是，确定SUMO化途径在疾病中的作用将有助于了解致病性 机制，并加速发现疾病修饰疗法的靶点。遗传和生物化学方法将与小鼠行为和神经病理学变化的表征相结合，以确定多聚Q AR SUMO化在SBMA敲入小鼠模型中的作用。这些研究通过确定SUMO化在SBMA中的作用，从而确定潜在的治疗靶点，预计将产生显著的积极影响。由于SUMO靶向了几种神经退行性疾病引起的蛋白质，我们预计我们的研究结果也将作为了解SUMO化对这些相关疾病表型影响的范例。

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.