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

描述（由申请人提供）：体育锻炼与帕金森病（PD）的风险呈负相关，并且在啮齿动物中可以防止MPTP诱导的线粒体功能障碍和神经元损失。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”小鼠具有显着的保护作用。在这些小鼠中，体细胞mtDNA突变加速积累，导致过早衰老表型。这些小鼠的运动使肌肉线粒体功能正常化，并显着延长寿命。也许更令人惊讶的是，体育锻炼还可以改善脑线粒体功能，完全防止脑萎缩。大脑中这些保护作用的机制尚不清楚。在骨骼肌中，运动增加了PGC-1的mRNA水平，PGC-1是一种转录辅激活因子，可以上调线粒体生物合成和抗氧化防御。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RIP 140的水平，RIP 140是PGC-1的活性抑制剂，并诱导PGC-1的SIRT 1依赖性脱乙酰化，从而促进其活化。我们推测，运动对脑线粒体功能的保护作用运动可能是由于类似的机制，解释了这种作用在肌肉。如果正确的话，那么这些机制可以解释运动与PD风险降低的关联。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PD发病机制中脑PGC-1活性降低。因此，增加脑中的PGC-1是一种有前途的潜在神经保护策略。Polg mutator小鼠是研究运动对大脑保护作用的有价值的模型。除了脑萎缩和受损 通过研究线粒体功能，我们有初步数据表明Polg突变小鼠具有显著的行为（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和多巴胺（DA）和多巴胺代谢物的减少，表明由体细胞mtDNA突变积累引起的线粒体功能障碍可导致黑质-纹状体病理学。这些数据提出了一种可能性，即我们和其他人在PD的SN神经元中发现的高水平的体细胞mtDNA突变可能有助于PD的黑质-纹状体功能障碍。因此，如果我们的假设被证明是正确的，那么关于运动对脑中体细胞mtDNA突变和PGC-1？活性影响的拟议研究可能与PD相关。该项目的主要目标是研究体育锻炼对Polg mutator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PGC-1水平和大脑活性的调节。这种有针对性的方法将得到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作用联系起来的新途径的作用。 公共卫生相关性：体育锻炼可以改善线粒体功能，并对大脑具有强大的保护作用，但这些作用的机制尚不清楚。了解这些机制提供了对与衰老和年龄相关的神经退行性疾病（如帕金森病）相关的新型神经保护策略的见解。我们现在建议通过对小鼠早衰模型的研究来研究运动对大脑的保护机制。

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. PUBLIC HEALTH RELEVANCE: Physical exercise improves mitochondrial function and has robust protective effects in the brain, but the mechanisms of these effects are unknown. Understanding these mechanisms provide insights into novel neuroprotective strategies of relevance to aging and age-related neurodegenerative diseases such as Parkinson's disease. We now propose to investigate the mechanisms of protection in the brain by exercise through studies of a mouse model of premature aging.