Mitochondrial Dysfunction and Progressive Encephalomyopathies

描述（由申请人提供）：ATP 6蛋白作为氢离子通道发挥作用，将离子转运与旋转ATP催化偶联。人类ATP 6基因中的错义突变被认为引起至少三种相关的和破坏性的综合征，其特征在于进行性肌肉损伤和神经系统症状：NARP（神经病、共济失调和色素性视网膜炎）、MILS（母系遗传的利氏综合征）和FBSN（家族性双侧纹状体坏死），并导致几种其他年龄相关疾病的发病机制。我们已经分离出果蝇线粒体ATP 6基因的错义突变，并将其作为线粒体脑肌病的模型。我们建议利用这种遗传动物模型系统来阐明体内进行性脑肌病的病理生理基础。公共卫生相关性：线粒体疾病影响约1/4000人。目前还没有有效的药物治疗这些毁灭性的疾病。我们对这些进展性疾病的发病机制的理解是有限的，在很大程度上是由于缺乏这些疾病的动物模型。我们的模型系统捕获了这些疾病的许多相关特征，在一个顺从的遗传系统，这个建议的目的是研究这些疾病的发病机制。

DESCRIPTION (provided by applicant): The ATP6 protein functions as a hydrogen ion channel that couples ion transport with rotary ATP catalysis. Missense mutations in the human ATP6 gene are believed to cause at least three related and devastating syndromes characterized by progressive muscle impairment and neurological symptoms: NARP (neuropathy, ataxia, and retinitis pigmentosa), MILS (maternally inherited Leigh's syndrome) and FBSN (familial bilateral striatal necrosis) and contribute to the pathogenesis of several other age-related diseases. We have isolated a missense mutation within the mitochondrial ATP6 gene of Drosophila and developed this as model of mitochondrial encephalomyopathy. We propose to utilize this genetic animal model system to elucidate the pathophysiological basis for progressive encephalomyopathies in vivo. PUBLIC HEALTH RELEVANCE: Mitochondrial disease affect ~ 1 in 4000 individuals. Currently there exists no effective pharmacotherapy for these devastating diseases. Our understanding of disease pathogenesis of these progressive conditions is limited, in large part due to a lack of animal models of these diseases. Our model system captures many relevant features of these diseases in an amenable genetic system and this proposal aims to study pathogenesis of these diseases.