Probing Neurodegeneration with Drosophila

该项目的最终目标是确定 脊髓小脑常见的发病机制和潜在的治疗靶点 共济失调(SCA)。这些是一组遗传上不同的神经退行性变 具有共同的神经病理和临床特征的疾病，如脑萎缩 小脑和运动协调和平衡的丧失。 最近的数据表明，遗传性共济失调之间存在意想不到的联系。首先，一种蛋白质-- 遗传性共济失调的相互作用网络揭示了许多导致共济失调的因素 蛋白质共享相互作用的伙伴。第二，dAaxin-2(蛋白质的同源异构体 负责SCA2)是Aaxin-1[82Q]诱导的神经毒性的主要修饰物 SCA1果蝇模型。综上所述，这些观察表明，SCA和 也许其他遗传性共济失调可能具有共同的发病分子机制。 此外还有相似的神经病理和临床特征。这一假说预言 SCA有共同的基因修饰物和潜在的治疗靶点 未知。检验这一假说需要对遗传修饰物进行彻底的比较 不同遗传性共济失调的发病机制。 将使用遗传方法来确定引起神经毒性的修饰物。 通过扩展的Aaxin-1、Aaxin-2和Aaxin-7，负责SCA1、SCA2的蛋白质 SCA7。这里提出的工作将涉及以下具体目标：1) 探讨dAaxin-2功能部分丧失的分子机制 抑制Aaxin-1[82Q]诱导的神经退行性变。2)共济失调筛查 Aaxin-1[82Q]诱导的神经毒性的遗传修饰物的相互作用组。3)测试 Aaxin-1[82Q]遗传修饰物与果蝇模型共济失调的相互作用 SCA2和SCA7。4)调查选定的遗传修饰物，这些修饰物是 果蝇SCA模型。 这些比较研究对于哺乳动物模型来说是不切实际的，但却是可行的 利用果蝇。神经退行性变的抑制因子被确认为这一结果 研究可能直接指向特定的治疗目标。这些基础研究是 为这些神经退行性疾病开发治疗方法的先决条件 目前还没有有效的治疗方法。

The ultimate goal of this project is to identify molecular mechanisms of pathogenesis and potential therapeutic targets that are common to Spinocerebellar ataxias (SCAs). These are a group ~30 genetically heterogeneous neurodegenerative disorders that share neuropathological and clinical features such as atrophy of the cerebellum and loss of motor coordination and balance. Recent data points to unsuspected links among inherited ataxias. First, a proteinprotein- interaction network for inherited ataxias revealed that many ataxia-causing proteins share interacting partners. Second, dAtaxin-2 (an orthologue of the protein responsible for SCA2) is a major modifier of Ataxin-1[82Q]-induced neurotoxicity in a Drosophila model of SCA1. Together, these observations suggest that SCAs, and perhaps other inherited ataxias may share molecular mechanisms of pathogenesis in addition to similar neuropathology and clinical features. This hypothesis predicts that SCAs have common genetic modifiers and potential therapeutic targets that remain unknown. Testing this hypothesis requires a thorough comparison of genetic modifiers and mechanisms of pathogenesis among different inherited ataxias. A genetic approach will be employed to identify modifiers of neurotoxicity caused by expanded Ataxin-1, Ataxin-2 and Ataxin-7, the proteins responsible for SCA1, SCA2 an SCA7. The work proposed here will address the following specific aims: 1) To investigate the molecular mechanisms by which partial loss of dAtaxin-2 function suppresses Ataxin-1[82Q]-induced neurodegeneration. 2) To screen the ataxia interactome for genetic modifiers of Ataxin-1[82Q]-induced neurotoxicity. 3) To test the Ataxin-1[82Q] genetic modifiers and the ataxia interactome in Drosophila models of SCA2 and SCA7. 4) To investigate selected genetic modifiers that are common to the Drosophila SCA models. These comparative studies are impractical with mammalian models, but feasible using Drosophila. The suppressors of neurodegeneration identified as a result of this work may directly point to specific therapeutic targets. These basic studies are prerequisite to developing therapies for these neurodegenerative disorders for which there are no effective treatments.