MITOCHONDRIAL ETIOLOGIES OF PARKINSON'S DISEASE

我们的中心致力于解决线粒体DNA遗传异常在帕金森病(PD)中的作用。帕金森病是成人中第二常见的神经退行性疾病，困扰着大约100万美国人。帕金森病缩短了预期寿命，对生活质量产生了不利影响。虽然突触核蛋白突变的罕见家族已经被描述，但在绝大多数病例中，帕金森病的原因尚不清楚。传统的孟德尔遗传因素似乎对病因学没有显著影响。此外，目前已确定的环境风险因素似乎在影响帕金森病发病风险方面的作用也微乎其微。本中心的研究人员首先提出了一种假说，即遗传性线粒体DNA异常可能在帕金森病中起致病作用，并解释了其零星出现的原因。他们首次证明帕金森病患者存在线粒体复合体I合成缺陷。他们首次采用线粒体转基因细胞质杂交(Cybrid)技术复制神经细胞，并利用Cybrid技术证明PD的复杂I合成缺陷是线粒体DNA异常的结果。我们小组是第一个证明线粒体DNA(MtDNA)的遗传突变可以在一个完全通过母系传播的多代家庭中导致帕金森病的人，并且第一个提供了在帕金森病中母系传播占主导地位的证据。我们中心的研究人员首次发现，胞质中的PD线粒体导致细胞内钙信号异常，氧化应激增加，线粒体膜电位降低，NFkappaB基因激活增加，线粒体运动和形态发生改变。这些对细胞功能和存活的重要生物学后果可能代表了PD mtDNA突变如何增加PD神经元死亡风险的机制。这一科学进步的记录，再加上线粒体DNA的遗传异常构成了大多数帕金森病的合理病因的知识，突显了这些建议在这一应用中的重要性。在本申请的四个项目中，我们将对帕金森病患者的线粒体DNA进行测序，表征帕金森病患者线粒体结构和功能的异常，阐明帕金森病的遗传流行病学，并阐明线粒体功能障碍与神经元死亡的关系。这些研究的结果可能导致临床前的诊断程序和特定的治疗方法来阻止帕金森病的神经元死亡。

Our Center is dedicated to resolving the role of inherited abnormalities in mitochondrial DNA in Parkinson's Disease (PD). PD is the second most prevalent neurodegenerative disorder of adults and afflicts about 1 million Americans. Life expectancy is shortened and quality of life is adversely affected by PD. While rare families with mutations in synuclein proteins have been described,, the cause of PD in the vast majority of cases is unknown. Traditional Mendelian genetic factors do not appear to contribute prominently to etiology. Furthermore, currently identified environmental risk factors also appear to play a minimal role in influencing the risk of developing PD. Investigators in our Center first articulated the hypothesis that inherited mitochondrial DNA abnormalities might play a pathogenic role in PD and account for its sporadic appearance. They were first to demonstrate a mitochondrial Complex I synthetic defect in PD. They were the first to adapt the mitochondrial transgenic cytoplasmic hybrid ("cybrid") technique to replicating neural cells and to use cybrid technology to demonstrate that the complex I synthetic defect in PD occurred as a consequence of abnormalities in mitochondrial DNA. Our group was the first to demonstrate that an inherited mutation in mitochondrial DNA (mtDNA) could contribute to PD in a multi-generational family with exclusively matrilineal transmission, and the first to provide evidence of a predominance of maternal transmission in PD. Investigators in our Center were the first to show that PD mitochondria in cybrids produced abnormalities in intracellular calcium signaling, increased oxidative stress, depressed mitochondrial membrane potential, increased NFkappaB gene activation and altered mitochondrial movement and morphology. These important biological consequences for cell function and survival may represent mechanisms of how PD mtDNA mutations increase risk of neuronal death in PD. This track record of scientific progress, coupled with the knowledge that inherited abnormalities of mitochondrial DNA constitute a plausible etiology for most cases of PD, underscore the significance of the proposals in this application. In the four Projects in this application we will sequence mitochondrial DNA in subjects with PD, characterize abnormalities of mitochondrial structure and function in PD, clarify the genetic epidemiology of PD, and elucidate the relationship between mitochondrial dysfunction and neuronal death. Results of these studies may lead to preclinical diagnostic procedures and specific therapies to halt neuronal death in PD.