Neurodegeneration with Drosophila

描述（改编自申请人摘要）：本研究的最终目标 项目是通过以下方式深入了解聚谷氨酰胺诱导的神经变性： 确定参与的基因，途径和分子机制， 脊髓小脑共济失调1型（SCA 1）的发病机制。一个果蝇模型， SCA 1是通过产生表达正常或扩增的果蝇而产生的。 人SCA 1转基因。这种果蝇模型概括了 在SCA 1患者中观察到的包括核包涵体（NI）的形成 和进行性神经元变性利用果蝇的力量 遗传学，两个大的遗传筛选被设计来识别基因，修改 眼内的SCA 1神经退行性表型。第一次筛选 当基因活性降低时，SCA 1表型的修饰剂;第二种修饰剂 当基因活性增加时，筛选产生SCA 1修饰物。两 神经退行性表型的抑制子和增强子获自 每个屏幕。这项工作的第一个目标是确定那些 修饰SCA 1神经退行性表型。这些修改将进一步 其特征在于灵敏的活力和迁移率测定， 量化其修饰效果。最强大的抑制剂将是 选择进一步研究。为了研究不同的聚谷氨酰胺 疾病共享共同的发病机制，SCA 1修饰剂将是 在亨廷顿病和多聚谷氨酰胺毒性的苍蝇模型中进行了测试。最后， 因为SCA 1基因的正常功能可能与发病机制有关， 果蝇SCA 1基因的功能将通过产生来研究 缺乏功能的突变和转基因的过度表达。 在未来的研究中，最有前途的SCA 1抑制剂在苍蝇中的特点， 将在SCA 1小鼠模型中以及在 多谷氨酰胺病这些基因也可能与旨在 治疗其它神经变性蛋白质病如阿尔茨海默病， 帕金森病。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.