Molecular Genetic Analysis of Neurodegeneration

描述（由申请人提供）：许多人类神经退行性疾病知之甚少且无法治疗，包括帕金森氏病、阿尔茨海默氏病和亨廷顿病。对于这些疾病的一些家族形式，已知与疾病相关的特定基因产物中的突变，从而允许在简单系统中对疾病进行建模，以解决退化机制并开拓新的治疗方法。为此，我们采用了一种新的方法来解决多聚谷氨酰胺诱导的神经退行性疾病的问题，通过在果蝇中建立这类人类疾病的模型。这些实验表明，聚谷氨酰胺诱导的神经变性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，以解决变性机制并定义新的治疗方法。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，是在体内的神经变性的有效调制器。 我们现在建议将果蝇强大的分子遗传学应用于遗传筛选，以发现神经变性的其他调节剂。遗传筛选的优点是，它们提供了定义可以影响和调节发病机制的基因的能力，而不需要先前对所涉及的机制的了解。具体的目的是定义新的调制器的神经变性的错误表达和功能丧失的遗传筛选，并从分子上定义和生物学上表征这些修改器，以解决他们的分子和生物学模式的行动。通过应用果蝇分子遗传学的力量来解决聚谷氨酰胺诱导的变性的保守特征，这些研究为治愈和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.