Molecular Genetic Analysis of Neurodegeneration

描述(申请人提供)：许多人类神经退行性疾病知之甚少，也无法治疗，包括帕金森氏症、阿尔茨海默氏症和亨廷顿氏症。对于这些疾病的一些家族性形式，与疾病相关的特定基因产物的突变是已知的，这使得有可能在简单的系统中对疾病进行建模，以便解决退化机制和开拓新的治疗方法。为此，我们应用了一种新的方法来解决多谷氨酰胺诱导的神经退化问题，在果蝇身上开发了一种针对这类人类疾病的模型。这些实验表明，多聚谷氨酰胺诱导的果蝇神经退行性变的基本分子机制在果蝇中是保守的，因此，果蝇遗传学可以应用于研究这些人类疾病，以解决退行性疾病的机制和确定新的治疗方法。利用这个模型，我们已经证明了分子伴侣是高度保守的蛋白质，是体内神经退行性变的强有力的调节器。 我们现在建议将果蝇强大的分子遗传学应用于遗传筛选，以揭示神经退化的额外调节器。基因筛查的优势在于，它们提供了定义可以影响和调节发病机制的基因的能力，而不需要事先了解所涉及的机制。其具体目的是在错误表达和功能丧失的遗传筛选中定义新的神经退行性变调节剂，并从分子上定义和生物学表征这些调节剂，以解决它们的分子和生物学作用模式。通过应用果蝇分子遗传学的力量来解决多谷氨酰胺诱导的变性的保守特征，这些研究为治疗人类神经退行性疾病的新方法提供了基础。

DESCRIPTION (provided by applicant): Many human neurodegenerative diseases are poorly understood as well as untreatable, including Parkinson's, Alzheimer's and Huntington's diseases. For some familial forms of these diseases, mutations in specific genes products associated with disease are known, allowing the possibility to model the disease in simple systems in order to address mechanisms of degeneration and to pioneer novel treatments. Toward this end, we applied a new approach to the problem of polyglutamine-induced neurodegeneration by developing a model for this class of human disease in the fruit fly Drosophila melanogaster. These experiments demonstrated that fundamental molecular mechanisms of polyglutamine-induced neurodegeneration are conserved in Drosophila, such that Drosophila genetics can be applied to investigate these human diseases in order to address mechanisms of degeneration and define new means of treatment. Using this model, we have shown that the molecular chaperones, which are highly conserved proteins, are potent modulators of neurodegeneration in vivo. We now propose to apply the powerful molecular genetics of Drosophila in genetic screens to uncover additional modulators of neurodegeneration. The advantage of genetic screens is that they provide the ability to define genes that can influence and modulate pathogenesis without requiring previous knowledge of the mechanisms involved. The specific aims are to define novel modulators of neurodegeneration in mis-expression and loss-of-function genetic screens, and to molecularly define and biologically characterize these modifiers in order to address their molecular and biological modes of action. By applying the power of Drosophila molecular genetics to address conserved features of polyglutamine-induced degeneration, these studies provide the foundation for new approaches to cures and treatments for human neurodegenerative disease.