Pathways of neurodegeneration in SBMA

长期目标是了解脊髓延髓肌萎缩症(SBMA)的分子基础，以便 治疗方法可能被开发出来。SBMA是一种以进行性运动丧失为特征的遗传性疾病 脑干和脊髓中的神经元。SBMA是由三核苷酸(CAG)重复序列在 雄激素受体(AR)基因导致AR蛋白中多谷氨酰胺的扩张。其他八种疾病 同样的突变：亨廷顿病、DR解放军和六种形式的脊髓小脑性共济失调。已扩展 聚谷氨酰胺本身就是有毒的。然而，尽管这种疾病的广泛和重叠的表现 这些疾病是通过不同神经元群体的选择性脆弱性来区分的。这 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。 这项提案的第一个目标将解决离散AR功能域在启动和 SBMA的发病机制。 在多谷氨酰胺疾病的发生和发展中的另一个重要决定因素是 负责保护细胞免受有毒蛋白质伤害的细胞机制。蛋白质的两条途径 降解，泛素-蛋白酶体系统(UPS)和自噬，已经被认为是起作用的 在多聚谷氨酰胺疾病中的重要作用。UPS是一个多组件系统，可以及时协调 以及胞内蛋白质的特定降解。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途径。在此的后两个目标中 建议，我们将测试与UPS和自噬在发病机制中的作用有关的特定假设 是SBMA的。 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2：验证SBMA发病机制与UPS受损相关的假设 在体内发挥作用。 目的3：用组织学和遗传学方法确定自噬在SBMA发病机制中的作用

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. Eight other diseases have the same kind of mutation: Huntington's disease, DRPLA, and six 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. Two 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 two 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