Probing Neurodegeneration with Drosophila

描述（由申请人提供）：该项目的最终目标是确定脊髓小脑共济失调（SCA）常见的发病机制和潜在治疗靶点的分子机制。这是一组约30种遗传异质性神经退行性疾病，具有共同的神经病理学和临床特征，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未知的联系。首先，遗传性共济失调的蛋白质-蛋白质相互作用网络揭示了许多引起共济失调的蛋白质共享相互作用的伴侣。第二，dAtaxin-2（负责SCA 2的蛋白质的直向同源物）是SCA 1的果蝇模型中Ataxin-1[82 Q]诱导的神经毒性的主要修饰剂。总之，这些观察结果表明，SCA，也许其他遗传性共济失调可能共享分子机制的发病机制，除了类似的神经病理学和临床特征。这一假说预测，SCA具有共同的遗传修饰剂和潜在的治疗靶点，这些靶点仍然未知。验证这一假设需要彻底比较遗传修饰剂和发病机制之间的不同遗传性共济失调。将采用遗传方法来鉴定由扩展的共济失调蛋白-1、共济失调蛋白-2和共济失调蛋白-7（负责SCA 1、SCA 2和SCA 7的蛋白质）引起的神经毒性的修饰剂。本研究的主要目的是：1）研究dAtaxin-2功能的部分缺失抑制Ataxin-1[82 Q]诱导的神经退行性变的分子机制。2)筛选共济失调相互作用基因组中共济失调蛋白-1（Ataxin-1）[82 Q]诱导神经毒性的遗传修饰物。3)在SCA 2和SCA 7的果蝇模型中检测Ataxin-1[82 Q]遗传修饰物和共济失调相互作用组。4)在SCA 1基因敲入小鼠模型中验证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是不切实际的哺乳动物模型，我们将使用果蝇模型的大部分分析和小鼠模型的关键相互作用的验证。作为这项工作的结果，神经变性的抑制因子可能直接指向特定的治疗靶点。这些基础研究是为这些没有有效治疗方法的神经退行性疾病开发治疗方法的先决条件。公共卫生相关性：本研究旨在揭示脊髓小脑性共济失调的发病机制和潜在的治疗靶点。这些基础研究是为这些没有有效治疗方法的神经退行性疾病开发治疗方法的先决条件。

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.