Pathways of neurodegeneration in SBMA

描述（由申请人提供）：长期目标是了解脊髓球性肌萎缩症（SBMA）的分子基础，以便开发治疗方法。SBMA是一种以脑干和脊髓运动神经元进行性丧失为特征的遗传性疾病。SBMA是由雄激素受体（AR）基因中的三核苷酸（CAG）重复扩增导致AR蛋白中的聚谷氨酰胺扩增引起的。其他8种疾病也有相同的突变：亨廷顿氏病、DRPLA和6种脊髓小脑性共济失调。膨化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，这些疾病是通过不同神经元群体的选择性易感性来区分的。这一观察结果表明，膨化聚谷氨酰胺不能是神经变性的唯一决定因素。本提案的第一个目标将解决离散AR功能域在SBMA的启动和发病机制中的作用。在多聚谷氨酰胺疾病的发生和发展中，另一个重要的决定因素是负责保护细胞免受有毒蛋白侵害的细胞机制的状态。两种蛋白质降解途径，即泛素-蛋白酶体系统（UPS）和自噬，在多聚谷氨酰胺疾病中起重要作用。UPS是一个多组分系统，协调细胞内蛋白质的及时和特异性降解。自噬是一种溶酶体介导的分解代谢途径，是细胞质成分大量降解的主要手段。在本提案的第二个目标中，我们将检验与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展AR毒性的贡献。

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.