Mitochondrial Dysfunction in Neurodegeneration and Compensatory Approaches

描述（由申请人提供）：一生中线粒体氧化磷酸化功能的逐渐下降可能是神经变性的一个因素。然而，对线粒体缺陷的机制的理解仍然是初级的，并且没有实际的方法来减轻这一问题。我们的项目将研究线粒体参与神经变性和衰老的这两个方面。在第一部分中，我们建议研究线粒体DNA （mtDNA）缺失在大脑衰老中的作用。我们将使用我们实验室开发的一种新型小鼠，其中线粒体靶向限制性内切酶（Mito-PstI）以组织特异性和诱导的方式表达。Mito-PstI引发的双链断裂导致重组和缺失的形成。我们将在中枢神经系统或无处不在地产生mtDNA缺失。线粒体聚合酶γ在修复这些双链断裂中的作用也将被分析。这个目的的目的是研究在神经变性和衰老过程中积累不同水平的mtDNA缺失的功能后果。在提案的第二部分，我们将开发通过增加骨骼肌或无处不在的PGC-1a表达来减轻中枢神经系统和其他组织衰老的方法。这将通过稳定和诱导的表达来实现。PGC-1a的作用将在正常衰老的小鼠和校对缺陷聚合酶γ“突变小鼠”中进行测试。后者是加速老化的一种模式。这两个目标都是基于广泛的已发表和未发表的初步数据。我们相信，这两个目标的实现不仅会使我们更好地了解线粒体缺陷在与年龄相关的神经退行性变中的作用，而且还会带来新的方法来抵消这些影响。

DESCRIPTION (provided by applicant): A progressive decline in mitochondrial oxidative phosphorylation function during life is a likely contributor to neurodegeneration. However, the understanding of the mechanisms involved in the mitochondrial defects is still rudimentary and practical approaches to mitigate this problem are not available. Our project will study these two aspects of mitochondrial involvement in neurodegeneration and aging. In the first part, we propose to study the role of mitochondrial DNA (mtDNA) deletions in the aging of the brain. We will use a novel mouse developed in our laboratory in which a mitochondria targeted restriction endonuclease (Mito-PstI) is expressed in a tissue-specific and inducible fashion. The double-strand breaks elicited by Mito-PstI lead to recombination and deletion formation. We will generate mtDNA deletions in the CNS or ubiquitously. The role of the mitochondrial polymerase gamma in repairing these double-strand breaks will also be analyzed. The goal of this aim is to study the functional consequences of accumulating different levels of mtDNA deletions during neurodegeneration and aging. In the second part of the proposal, we will develop approaches to mitigate the aging of CNS and other tissues by increasing the expression of PGC-1a, either in skeletal muscle or ubiquitously. This will be achieved by stable and inducible expression. The effect of PGC-1a will be tested both in normal aging mice and in the proof-reading deficient polymerase gamma "mutator mouse". The latter is a model of accelerated aging. Both aims are based on extensive published and unpublished preliminary data. We are confident that the accomplishment of these two aims will lead to not only a better understanding of the role of mitochondrial defects in age-related neurodegeneration but also to novel approaches to counteract these effects. PUBLIC HEALTH RELEVANCE: Mitochondria is believed to play a major role in neurodegeneration and aging. By better understanding the mechanisms involved in this process and by developing approaches to counteract these effects, the debilitating effects of the neurodegenerative process could be mitigated.