How does mitochondrial dysfunction cause neurodegeneration?

描述(申请人提供)：线粒体功能障碍与许多神经退行性疾病有关，包括帕金森氏病、阿尔茨海默病和肌萎缩侧索硬化症等。然而，相对于其他细胞和分子机制，线粒体功能障碍在退行性变中的确切作用尚不清楚。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化。这项建议开发了一种新的果蝇Leigh病模型，并使用该系统中可用的强大的遗传、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，包括对细胞新陈代谢的影响，以及过度产生活性氧物种(ROS)，将线粒体功能的改变与神经元退化联系起来。先前的工作表明，线粒体功能障碍会触发两个不同的基因退化过程。其中一条途径依赖于ROS的产生，并特异性地导致突触丢失，而另一条途径不依赖ROS，导致细胞体结构退化。这项提案涉及以下问题。ROS是激活了导致退变的信号，还是起到了慢性损伤的作用，或者两者兼而有之？线粒体功能障碍导致神经退行性变的分子靶点是什么？神经退行性疾病困扰着许多人，仅帕金森氏症一项就影响了100多万美国人。然而，目前大多数神经退行性疾病的治疗选择非常有限。动物模型提供了对神经退行性疾病特定方面潜在的基本分子机制的新理解，并在确定新的药物靶点方面发挥了重要作用。通过开发一种新的果蝇线粒体脑病模型，这一提议将大大有助于我们对神经退行性疾病的基本理解，并将识别调节疾病进展的新蛋白质。 与公共卫生相关：帕金森氏症、阿尔茨海默病和肌萎缩侧索硬化症等神经退行性疾病困扰着数百万美国人，但现有的治疗方法效果有限。这项建议开发了一种新的神经退行性疾病的动物模型，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目标，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.