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， 治疗可以发展。SBMA是一种以运动功能进行性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）重复扩增引起的， 雄激素受体（AR）基因导致AR蛋白中的多聚谷氨酰胺扩增。其他八种疾病 相同类型的突变：亨廷顿氏病，DRPLA和六种形式的脊髓小脑共济失调。扩大 聚谷氨酰胺本身是有毒的。然而，尽管疾病的广泛和重叠表达， 蛋白质，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 观察表明，扩增的多聚谷氨酰胺不是神经变性的唯一决定因素。 该提案的第一个目的将解决离散AR功能结构域在启动中的作用， SBMA的发病机制。 在多聚谷氨酰胺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侵害的细胞机制。蛋白质的两条途径 降解，泛素-蛋白酶体系统（UPS）和自噬，已被牵连作为发挥 在多聚谷氨酰胺疾病中的重要作用。UPS是一个多组件系统， 和细胞内蛋白质的特异性降解。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。在第二个目标中， 根据这项提议，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。 关于SBMA 目的1：定义特定AR结构域对聚谷氨酰胺扩展AR毒性的贡献。 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：通过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