Genetic Analysis of Neurodegeneration in Drosophila

描述(申请人提供)：神经退行性变的特征是神经元功能的进行性丧失，导致可能导致死亡的身体和认知缺陷。阿尔茨海默氏症等神经退行性疾病是一个重大的健康问题。目前，还没有有效的方法来预防任何疾病的神经退行性变。我们想了解一种罕见的疾病共济失调-毛细血管扩张症(A-T)所需的分子和细胞事件，这种疾病是由A-T突变(ATM)基因突变引起的。在A-T中，神经退化在两岁之前就开始了，并随着年龄的增长而恶化。以黑腹果蝇为实验模型，对A-T进行了研究。到目前为止，我们已经发现神经元中的ATM突变扰乱了细胞周期调节，导致静止的神经元重新进入有丝分裂细胞周期并死亡。我们还发现，神经胶质细胞中的ATM突变通过核因子B转录因子激活先天免疫反应，从而导致神经元死亡。这些在苍蝇身上的发现与人类有关。神经细胞周期的重新进入和先天免疫反应的激活发生在患有A-T的个体以及患有其他神经退行性疾病如阿尔茨海默氏症的个体中。在拟议的研究中，我们将继续使用苍蝇，因为它们是目前可用的唯一由于ATM突变而经历神经退行性变的动物模型。此外，苍蝇体内可用的分子和遗传工具使快速研究神经退行性变的分子和途径成为可能，为开发靶向治疗提供了框架。为了阐明A-T中导致神经退行性变的事件的途径，我们提出：(1)确定激活ARIST导致ATM突变果蝇神经退行性变的因素和信号事件；(2)确定ARISH AT的转录靶标是导致ATM突变型果蝇神经退行性变的必要条件和充分条件。

DESCRIPTION (provided by applicant): Neurodegeneration is characterized by the progressive loss of neuron function resulting in physical and cognitive defects that can cause death. Neurodegenerative diseases such as Alzheimer's are a substantial health issue. Currently, there is no effective means to prevent neurodegeneration in any disease. We want to understand the molecular and cellular events that are required for neurodegeneration in a rare disease Ataxia-telangiectasia (A-T), which is caused by mutation of the A- T mutated (ATM) gene. In A-T, neurodegeneration begins before the age of two and worsens with age. We have used Drosophila melanogaster as an experimental model to study A-T. To date, we have found that ATM mutations in neurons disrupt cell cycle regulation, which causes quiescent neurons to reenter the mitotic cell cycle and die. We have also found that ATM mutations in glial cells activate the innate immune response through the NF-¿B transcription factor Relish, which causes neurons to die. These findings in flies are relevant to humans. Neuron cell cycle reentry and activation of the innate immune response occur in individuals with A-T as well as in individuals with other neurodegenerative diseases such as Alzheimer's. In the proposed studies, we will continue to use flies because they are the only animal model currently available that undergoes neurodegeneration as a result of ATM mutation. Moreover, the arsenal of molecular and genetic tools available in flies make it possible to rapidly investigate the molecules and pathways that underlie neurodegeneration, providing a framework for developing targeted therapies. To delineate the pathway of events that cause neurodegeneration in A-T we proposed to: (1) determine the factors and signaling events that activate Relish to cause neurodegeneration in ATM mutant flies and (2) determine the transcription targets of Relish at are necessary and sufficient to cause neurodegeneration in ATM mutant flies.