Pathways of neurodegeneration in SBMA

描述（由申请人提供）：长期目标是了解脊髓延髓肌萎缩症（SBMA）的分子基础，以便开发治疗方法。SBMA是一种遗传性疾病，其特征是脑干和脊髓中运动神经元的进行性丧失。SBMA是由雄激素受体（AR）基因中的三核苷酸（CAG）重复扩增引起的，导致AR蛋白中的多聚谷氨酰胺扩增。其他8种疾病也有同样的突变：亨廷顿病、DRPLA和6种脊髓小脑共济失调。扩展的聚谷氨酰胺本身是有毒的。然而，尽管疾病蛋白的广泛和重叠表达，这些疾病的区别在于不同群体的神经元的选择性脆弱性。这一观察结果表明，扩展的聚谷氨酰胺不能是神经变性的唯一决定因素。该建议的第一个目的是解决离散AR功能域在SBMA的启动和发病机制中的作用。多聚谷氨酰胺病的发生和发展的另一个重要决定因素是负责保护细胞免受有毒蛋白质侵害的细胞机制的状态。泛素-蛋白酶体系统（UPS）和自噬是蛋白质降解的两条途径，在多聚谷氨酰胺疾病中起着重要作用。UPS是一种多组分系统，其协调细胞内蛋白质的及时和特异性降解。自噬是溶酶体介导的分解代谢途径，是细胞质组分大量降解的主要手段。在本提案的第二个目标中，我们将测试与UPS和自噬在SBMA发病机制中的作用有关的特定假设。目的1：确定特定AR结构域对聚谷氨酰胺扩增AR毒性的贡献。 目的2：验证SBMA发病机制与体内UPS功能受损相关的假设。目的3：利用组织学和遗传学方法确定自噬在SBMA发病机制中的作用。

DESCRIPTION (provided by applicant): The long-term goal is to understand the molecular basis of spinobulbar muscular atrophy (SBMA) so that treatment may be developed. SBMA is a hereditary disease characterized by progressive loss of motor neurons in the brainstem and spinal cord. SBMA is caused by trinucleotide (CAG) repeat expansion in the androgen receptor (AR) gene leading to polyglutamine expansion in AR protein. 8 other diseases have the same kind of mutation: Huntington's disease, DRPLA, and 6 forms of spinocerebellar ataxia. Expanded polyglutamine itself is toxic. However, despite widespread and overlapping expression of the disease proteins, these disorders are distinguished by selective vulnerability of different populations of neurons. This observation indicates that expanded polyglutamine cannot be the sole determinant of neurodegeneration. The first aim of this proposal will address the role of discrete AR functional domains in the initiation and pathogenesis of SBMA. Another important determinant in the initiation and progression of polyglutamine disease is that status of the cellular mechanisms responsible for protecting cells from toxic proteins. 2 pathways of protein degradation, the ubiquitin-proteasome system (UPS) and autophagy, have been implicated as playing important roles in polyglutamine diseases. The UPS is a multi-component system that coordinates timely and specific degradation of intracellular protein. Autophagy is a lysosome-mediated catabolic pathway and is the primary means of bulk degradation of cytoplasmic components. In the second 2 aims of this proposal, we will test specific hypotheses relating to the role of the UPS and autophagy in the pathogenesis of SBMA. Aim 1: Defining the contributions of specific AR domains to polyglutamine-expanded AR toxicity. Aim 2: To test the hypothesis that SBMA pathogenesis is associated with impaired UPS function in vivo. Aim 3: To determine the role of autophagy in SBMA pathogenesis using histological and genetic approaches.