Mitochondrial Dysfunction in Neurodegeneration and Compensatory Approaches

描述（由申请人提供）：生命期间线粒体氧化磷酸化功能的进行性下降可能是神经退行性变的原因。然而，对线粒体缺陷所涉及的机制的理解仍然是初步的，并且没有实用的方法来减轻这个问题。 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，我们打算研究线粒体DNA（mtDNA）缺失在脑老化中的作用。 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性方式表达。由Mito-Pst I引起的双链断裂导致重组和缺失形成。我们将在中枢神经系统中或普遍产生线粒体DNA缺失。还将分析线粒体聚合酶γ在修复这些双链断裂中的作用。本研究的目的是研究在神经退行性变和衰老过程中积累不同水平的mtDNA缺失的功能后果。在该提案的第二部分，我们将开发通过增加骨骼肌中或普遍存在的PGC-1a表达来减轻CNS和其他组织衰老的方法。这将通过稳定和诱导型表达来实现。PGC-1a的作用将在正常衰老小鼠和校对缺陷的聚合酶γ“突变小鼠”中进行测试。后者是加速老化的模型。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将导致更好地理解线粒体缺陷在年龄相关性神经退行性变中的作用，而且还将导致对抗这些影响的新方法。 公共卫生相关性：线粒体被认为在神经退行性变和衰老中起主要作用。通过更好地理解这一过程中涉及的机制，并通过开发抵消这些影响的方法，可以减轻神经退行性过程的衰弱效应。

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 Both aims are based on extensive published and unpublished preliminary data.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.