Neurodegeneration with Drosophila

描述(改编自申请人的摘要)：本报告的最终目标 该项目旨在通过以下方式深入了解聚谷氨酰胺引起的神经变性 确定参与该过程的基因、途径和分子机制 脊髓小脑性共济失调1型的发病机制。一种果蝇模型 SCA1是通过产生表达正常或扩展的果蝇而产生的 人类SCA1转基因。这个苍蝇模型概括了细胞的表型。 在SCA1患者中观察到的包括核内含物(NI)的形成 和进行性神经元变性。利用果蝇的力量 遗传学方面，设计了两个大的基因屏幕来识别修改基因 眼睛中的一种SCA1神经退行性表型。第一个屏幕出现了 当基因活性降低时SCA1表型的修饰物；第二 当基因活性增加时，筛选产生SCA1修饰物。两者都有 神经退行性变表型的抑制子和增强子是从 每个屏幕。这项拟议工作的第一个目标是识别 修改SCA1神经退行性变表型。这些修饰语将进一步 以灵敏的生存能力和运动能力检测为特征，允许 对它们的修饰效果进行量化。最强大的抑制者将是 被选中进行进一步研究。为了调查不同的聚谷氨酰胺 疾病具有共同的发病机制，SCA1修饰物将被 在亨廷顿病和多谷氨酰胺中毒的苍蝇模型上进行了测试。最后， 由于SCA1基因的正常功能可能与发病机制有关， 果蝇SCA1基因的功能将通过生成 功能缺失突变和转基因导致其过度表达。 在未来的研究中，最有希望的SCA1抑制子的特征是苍蝇 将在SCA1小鼠模型中进行研究，并在 多发性谷氨酰胺病。这些基因也可能与旨在 治疗其他神经退行性蛋白质病，如阿尔茨海默病和 帕金森氏症。他们将为未来提供有价值的目标 旨在开发治疗药物的药理学研究。

DESCRIPTION (Adapted from applicant's abstract): The ultimate goal of this project is to gain insight into polyglutamine-induced neurodegeneration by identifying genes, pathways and molecular mechanisms involved in the pathogenesis of spinocerebellar ataxia type 1 (SCA1). A Drosophila model of SCA1 was created by generating flies that express either normal or expanded human SCA1 transgenes. This fly model recapitulates the cellular phenotypes observed in SCA1 patients including the formation of nuclear inclusions (NI) and progressive neuronal degeneration. Capitalizing on the power of Drosophila genetics, two large genetic screens were designed to identify genes that modify a SCA1 neurodegenerative phenotype in the eye. The first screen yielded modifiers of the SCA1 phenotype when gene activity was decreased; the second screen yielded SCA1 modifiers when gene activity was increased. Both suppressors and enhancers of the neurodegenerative phenotype were obtained from each screen. The first aim of the proposed work is to identify the genes that modify the SCA1 neurodegenerative phenotype. These modifiers will be further characterized in sensitive viability and locomoter assays that allow the quantification of their modifier effects. The most powerful suppressors will be selected for further studies. To investigate whether different polyglutamine disease share common mechanisms of pathogenesis, the SCA1 modifiers will be tested in fly models of Huntington disease and polyglutamine toxicity. Finally, because the normal function of the SCA1 gene may be relevant to pathogenesis, the function of the Drosophila SCA1 gene will be investigated by generating lack-of-function mutations and transgenes for its over expression. In future studies, the most promising SCA1 suppressors characterized in flies will be investigated in the SCA1 mouse model, and in mouse models of polyglutamine disease. These genes may also be relevant to research aimed at treating other neurodegenerative proteinopathies such as Alzheimer disease and Parkinson disease. They will provide valuable targets for future pharmacological research aimed at developing drugs for therapy.