Molecular Genetic Analysis of Neurodegeneration

描述（由申请人提供）：许多人类神经退行性疾病，包括帕金森氏症、阿尔茨海默氏症和亨廷顿氏症，人们对它们知之甚少，也无法治疗。对于这些疾病的一些家族性形式，已知与疾病相关的特定基因产物的突变，从而有可能在简单系统中建立疾病模型，以便解决退化机制并开拓新的治疗方法。为此，我们通过在果蝇果蝇中建立这类人类疾病的模型，应用了一种新的方法来解决聚谷氨酰胺诱导的神经变性问题。这些实验表明，聚谷氨酰胺诱导的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，以解决退行性变的机制并确定新的治疗方法。使用这个模型，我们已经表明分子伴侣，这是高度保守的蛋白质，是体内神经退行性变的有效调节剂。

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.