How does mitochondrial dysfunction cause neurodegeneration?

描述（由申请人提供）：线粒体功能障碍与许多神经退行性疾病有关，包括帕金森病、阿尔茨海默病和肌萎缩性侧索硬化症等。然而，相对于其他细胞和分子机制，线粒体功能障碍在变性中的确切作用仍不清楚。然而，重要的是，罕见的遗传疾病，如Leigh病，直接影响线粒体功能，并导致婴儿和儿童的神经退行性变。该提案开发了一种新的果蝇Leigh病模型，并使用该系统中强大的遗传，行为和组织学工具来探索线粒体功能障碍导致退化的具体机制。 已经提出了几种替代机制，包括对细胞代谢的影响和活性氧（ROS）的过度产生，将线粒体功能的改变与神经元变性联系起来。以前的工作表明，线粒体功能障碍触发两个遗传上不同的退行性过程。这些途径之一是依赖于ROS的产生，并特别导致突触的损失，而另一个途径是ROS独立的，并导致细胞体结构的退化。这项建议涉及以下问题。活性氧是否激活了一个诱导退化的信号，或作为慢性损伤剂，或两者兼而有之？导致神经退行性变的线粒体功能障碍的分子靶点是什么？ 神经退行性疾病困扰着许多人，仅帕金森病就影响了超过100万美国人。然而，目前，大多数神经退行性疾病的治疗选择非常有限。动物模型为神经退行性疾病特定方面的基本分子机制提供了新的理解，并在确定新的药物靶点方面发挥了重要作用。通过开发果蝇线粒体脑病的新模型，该提议将大大有助于我们对神经退行性疾病的基本了解，并将识别调节疾病进展的新蛋白质。 公共卫生相关性：神经退行性疾病，如帕金森病、阿尔茨海默病和肌萎缩性侧索硬化症困扰着数百万美国人，但现有的治疗方法疗效有限。该提案开发了一种新的神经退行性疾病动物模型，并使用遗传和分子生物学技术来定义影响疾病进展的新机制。这些研究将为药物开发提供新的靶点，并将广泛地为治疗策略提供信息。

DESCRIPTION (provided by applicant): Mitochondrial dysfunction has been linked to a number of neurodegenerative diseases, including Parkinson's Disease, Alzheimer's Disease and Amyotrophic Lateral Sclerosis, among others. However, the precise role of mitochondrial dysfunction in degeneration, relative to other cellular and molecular mechanisms, remains unclear. Importantly, however, rare genetic conditions such as Leigh Disease directly affect mitochondrial function and cause neurodegeneration in infants and children. This proposal develops a novel model of Leigh Disease in the fruit fly, and uses the powerful genetic, behavioral and histological tools available in this system to probe the specific mechanisms by which mitochondrial dysfunction causes degeneration. Several alternate mechanisms, including effects on cellular metabolism, and the excessive production of reactive oxygen species (ROS) have been proposed to link alterations in mitochondrial function to neuronal degeneration. Previous work demonstrates that mitochondrial dysfunction triggers two genetically distinct degenerative processes. One of these pathways is dependent on ROS production, and leads specifically to synapse loss, while the other pathway is ROS-independent and causes degeneration of cell body structures. This proposal addresses the following questions. Do ROS activate a degeneration-inducing signal, or act as chronic damaging agents, or both? What are the molecular targets of mitochondrial dysfunction that lead to neurodegeneration? Neurodegenerative diseases afflict many people, with Parkinson's Disease alone affecting more than 1 million Americans. At present, however, treatment options for most neurodegenerative diseases are highly limited. Animal models have provided new understanding of the basic molecular mechanisms underlying specific aspects of neurodegenerative disease, and have played important roles in identifying new drug targets. By developing a new model of mitochondrial encephalopathy in the fruit fly, this proposal will contribute significantly both to our fundamental understanding of neurodegenerative disease, and will identify new proteins that regulate disease progression. PUBLIC HEALTH RELEVANCE: Neurodegenerative diseases like Parkinson's Disease, Alzheimer's Disease and Amyotrophic lateral sclerosis afflict millions of Americans, yet existing treatments are of only limited efficacy. This proposal develops a new animal model of neurodegenerative disease, and uses genetic and molecular biological techniques to define novel mechanisms affecting disease progression. These studies will provide new targets for drug development, and will broadly inform treatment strategies.