Probing Neurodegeneration with Drosophila

项目描述（由申请人提供）：本项目的最终目标是确定脊髓小脑共济失调（SCAs）常见的发病机制和潜在的治疗靶点。这是一组约30种遗传异质性的神经退行性疾病，它们具有相同的神经病理和临床特征，如小脑萎缩和运动协调和平衡丧失。最近的数据表明，遗传性共济失调之间存在着意想不到的联系。首先，遗传共济失调的蛋白质-蛋白质相互作用网络揭示了许多引起共济失调的蛋白质有共同的相互作用伙伴。其次，ataxin -2（负责SCA2的蛋白的同源物）是Ataxin-1[82Q]在SCA1果蝇模型中诱导的神经毒性的主要修饰物。总之，这些观察结果表明，除了相似的神经病理和临床特征外，SCAs和其他遗传性共济失调可能具有共同的分子发病机制。这一假说预测sca具有共同的遗传修饰因子和未知的潜在治疗靶点。为了验证这一假设，需要对不同遗传性共济失调的遗传修饰因子和发病机制进行彻底的比较。将采用遗传方法鉴定由扩展的Ataxin-1、Ataxin-2和Ataxin-7（负责SCA1、SCA2和SCA7）引起的神经毒性修饰因子。这里提出的工作将解决以下具体目标：1)研究dAtaxin-2功能的部分丧失抑制Ataxin-1[82Q]诱导的神经变性的分子机制。2)筛选共济失调相互作用组中Ataxin-1[82Q]诱导神经毒性的遗传修饰因子。3)在SCA2和SCA7果蝇模型中检测Ataxin-1[82Q]基因修饰因子和共济失调相互作用组。4)在敲入小鼠SCA1模型中验证Ataxin-2和Ataxin-1之间的遗传相互作用。由于这些广泛的比较研究与哺乳动物模型是不切实际的，我们将使用果蝇模型进行大部分分析，并使用小鼠模型验证关键相互作用。作为这项工作的结果，神经退行性疾病的抑制因子可能直接指向特定的治疗靶点。这些基础研究是开发治疗这些没有有效治疗方法的神经退行性疾病的先决条件。公共卫生相关性：本研究旨在揭示脊髓小脑共济失调的发病机制和确定潜在的治疗靶点。这些基础研究是开发治疗这些没有有效治疗方法的神经退行性疾病的先决条件。

DESCRIPTION (provided by applicant): 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 protein- protein-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 validate the genetic interaction between Ataxin-2 and Ataxin-1 in a knock-in mouse SCA1 model. Since these extensive comparative studies are impractical with mammalian models, we will use Drosophila models for the majority of the analysis and mouse models for validation of key interactions. 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. PUBLIC HEALTH RELEVANCE: The work in this proposal is aimed towards revealing mechanisms of pathogenesis and identifying potential therapeutic targets in Spinocerebellar ataxias. These basic studies are a prerequisite to developing therapies for these neurodegenerative disorders for which there are no effective treatments.