Pathways of neurodegeneration in SBMA

描述(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)基因的三核苷酸(CAG)重复扩增导致AR蛋白中多谷氨酰胺的扩增而引起的。其他8种疾病有相同的突变：亨廷顿病、DR解放军和6种形式的脊髓小脑性共济失调。膨胀的聚谷氨酰胺本身就是有毒的。然而，尽管疾病蛋白的表达广泛且重叠，但这些疾病的区别在于不同神经元群体的选择性脆弱性。这一观察表明，膨胀的聚谷氨酰胺不是神经退行性变的唯一决定因素。这项建议的第一个目的将解决离散的AR功能结构域在SBMA的启动和发病机制中的作用。在多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质伤害的细胞机制的状态。泛素-蛋白酶体系统(UPS)和自噬这两条蛋白质降解途径在聚谷氨酰胺疾病中起着重要作用。UPS是一个多组分系统，协调细胞内蛋白质的及时和特定降解。自噬是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方式。在这项提案的第二个2个目标中，我们将测试与UPS和自噬在SBMA发病机制中的作用相关的特定假说。目的1：明确特定AR结构域在聚谷氨酰胺扩展AR毒性中的作用。 目的：在体内验证SBMA发病机制与UPS功能受损有关的假说。目的：用组织学和遗传学方法研究自噬在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.