Mechanisms of Protection in the Brain by Physical Exercise in Polg Mutator Mice

描述(申请人提供)：体育锻炼与患帕金森氏病(PD)的风险成反比，在啮齿动物中，可以保护线粒体功能障碍和MPTP导致的神经元丢失。最近，运动也被证明对表达线粒体DNA(MtDNA)聚合酶(Polg)校对缺陷形式的Polg“Mutator”小鼠具有戏剧性的保护作用。在这些小鼠中，体细胞mtDNA突变加速积累，导致过早衰老表型。这些小鼠的运动可以使肌肉线粒体功能正常化，并显著延长寿命。或许更令人惊讶的是，体育锻炼还能改善大脑线粒体功能，完全防止脑萎缩。这些保护作用在大脑中的作用机制尚不清楚。在骨骼肌中，运动增加了PGC-1的mRNA水平，PGC-1是一种转录辅助激活因子，可以上调线粒体的生物生成和抗氧化防御。运动也可能通过翻译后机制增加PGC-1的活性。在肌肉中，运动降低了PGC-1的活性抑制因子RIP140的水平，并诱导SIRT1依赖的PGC-1的脱乙酰化，从而促进其激活。我们假设，运动对大脑线粒体功能的保护作用可能源于与肌肉类似的机制。如果正确，那么这些机制可能解释了锻炼与帕金森病风险降低之间的联系。运动和PGC-1活性增加之间的这种潜在联系特别令人兴奋，因为最近的数据表明，在帕金森病的发病机制中，BRAI PGC-1活性降低。因此，增加脑内PGC-1的含量是一种很有前途的神经保护策略。Polg突变小鼠是研究运动对大脑保护作用的一个有价值的模型。除了脑萎缩和受损 在线粒体功能方面，我们有初步数据表明Polg突变小鼠存在显著的行为(运动)缺陷以及纹状体酪氨酸羟化酶(TH)免疫染色强度的丧失，以及多巴胺(DA)和多巴胺代谢产物的减少，表明体细胞mtDNA突变积累导致的线粒体功能障碍可导致黑质-纹状体病理。这些数据提出了这样一种可能性，即我们和其他人在帕金森氏病黑质-纹状体功能障碍的黑质-纹状体神经元中发现了高水平的体细胞mtDNA突变。因此，如果我们的假设被证明是正确的，那么关于运动对大脑中体细胞mtDNA突变和PGC-1活性的影响的拟议研究可能与帕金森病有关。本项目的主要目的是研究体育锻炼对Polg突变小鼠大脑的保护作用的潜在机制，包括对体细胞mtDNA突变水平的影响以及对大脑中PGC-1水平和活性的调节。这种有针对性的方法将得到一种无偏见的代谢组学方法的补充，该方法可能揭示将运动与大脑保护效应联系起来的新途径的作用。

DESCRIPTION (provided by applicant): Physical exercise is inversely related to the risk of Parkinson's disease (PD), and in rodents can protect against mitochondrial dysfunction and neuronal loss induced by MPTP. Recently, exercise also has been shown to have a dramatic protective effect in Polg "mutator" mice expressing a proofreading deficient form of the mitochondrial DNA (mtDNA) polymerase ¿ (Polg). In these mice, there is an accelerated accumulation of somatic mtDNA mutations, leading to a premature aging phenotype. Exercise in these mice normalizes muscle mitochondrial function and significantly extends lifespan. Perhaps more surprisingly, physical exercise also improves brain mitochondrial function and completely prevents brain atrophy. The mechanisms of these protective effects in the brain are unknown. In skeletal muscle, exercise increases levels of mRNA of PGC-1¿, a transcriptional coactivator that upregulates mitochondrial biogenesis and antioxidant defenses. Exercise also may increase PGC-1¿ activity through posttranslational mechanisms. In muscle, exercise reduces levels of RIP140, a suppressor of PGC-1¿ activity, and induces SIRT1 dependent deacetylation of PGC-1¿, thereby promoting its activation. We hypothesize that the protective effects of exercise on brain mitochondrial function exercise may result from similar mechanisms that account for this effect in muscle. If correct, then these mechanisms may account for the association of exercise with a reduced risk of PD. This potential link between exercise and increased PGC-1¿ activity is particularly exciting in light of recent data implicating reduced brai PGC-1¿ activity in the pathogenesis of PD. Thus, increasing PGC-1¿ in brain is a promising potential neuroprotective strategy. The Polg mutator mice represent a valuable model for studying the protective effects of exercise on the brain. In addition to brain atrophy and impaired mitochondrial function, we have preliminary data indicating that the Polg mutator mice have significant behavioral (motor) deficits as well as loss of striatal tyrosine hydroxylase (TH) immunostaining intensity and reduced dopamine (DA) and dopamine metabolites, indicating that mitochondrial dysfunction caused by somatic mtDNA mutation accumulation can cause nigral-striatal pathology. These data raise the possibility that the high levels of somatic mtDNA mutations that we and others have identified in SN neurons in PD may contribute to nigral-striatal dysfunction in PD. Thus, if our hypothesis proves to be correct, then the proposed studies on the impact of exercise on somatic mtDNA mutations and PGC-1¿ activity in the brain may be of relevance to PD. The main goal of this project is to investigate potential mechanisms of the protective effect of physical exercise in the brain of Polg mutator mice, including the impact on somatic mtDNA mutation levels and on regulation of PGC-1¿ levels and activity in the brain. This targeted approach will be complemented by an unbiased metabolomics approach that may reveal a role for novel pathways linking exercise to protective effects in the brain.