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

Polg 突变小鼠体育锻炼的大脑保护机制

基本信息

批准号：
8453923
负责人：
DAVID K. SIMON
金额：
$ 26.1万
依托单位：
BETH ISRAEL DEACONESS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-25 至 2014-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8453923
关键词：
Accounting Acetylation Affect Aging Antioxidants Attenuated Behavioral Biogenesis Brain Brain-Derived Neurotrophic Factor Cloning Complement Corpus striatum structure DNA copy number DNA-Directed DNA Polymerase Data Deacetylation Dopamine Electron Transport Exercise Functional disorder GDNF gene Gene Targeting Goals Light Link Longevity Measures Messenger RNA Metabolic Pathway Metabolism Mitochondria Mitochondrial DNA Molecular Mus Muscle NRIP1 gene Neurites Neurodegenerative Disorders Neuroglia Neurons PGC1a Regulation Pathway Parkinson Disease Pathogenesis Pathology Pathway interactions Phenotype Phosphorylation Post-Translational Protein Processing Premature aging syndrome Proteins Regulation Risk Rodent Role Skeletal Muscle Study models Substantia nigra structure Transcription Coactivator Tyrosine 3-Monooxygenase Ventral Tegmental Area age related cerebral atrophy human FRAP1 protein improved insight laser capture microdissection mRNA Expression metabolomics mitochondrial DNA mutation mitochondrial dysfunction motor deficit mouse model neuron loss neuronal cell body novel prevent protective effect sedentary small molecule

项目摘要

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.

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 引起的线粒体功能障碍和神经元损失。最近，运动也被证明具有显着的保护作用。在表达线粒体 DNA (mtDNA) 聚合酶校对缺陷形式的 Polg“突变”小鼠中 ¿ （Polg）。在这些小鼠中，体细胞 mtDNA 突变加速积累，导致这些小鼠过早衰老的表型。也许更令人惊讶的是，体育锻炼还可以改善大脑线粒体功能。完全预防脑萎缩的机制尚不清楚。在骨骼肌中，运动会增加 PGC-1 的 mRNA 水平。，一种上调线粒体生物发生和抗氧化防御的转录共激活因子，运动也可能增加 PGC-1¿在肌肉中，运动会降低 PGC-1 抑制剂 RIP140 的水平。活性，并诱导 SIRT1 依赖性 PGC-1 脱乙酰化，从而促进其激活，我们认为运动对大脑线粒体功能的保护作用可能是由于在肌肉中产生这种作用的类似机制造成的，如果正确的话，那么这些机制可能可以解释运动与降低风险的关系。 PD。运动和 PGC-1 增加之间的潜在联系。鉴于最近的数据表明 brai PGC-1 减少，活动尤其令人兴奋。 PD 发病机制中的活性因此，增加 PGC-1¿ Polg 突变小鼠是研究运动对大脑的保护作用以及脑萎缩和受损的一个有价值的模型。对于线粒体功能，我们有初步数据表明 Polg 突变小鼠具有显着的行为（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）和多巴胺代谢物的减少，表明体细胞引起的线粒体功能障碍mtDNA 突变积累可能导致黑质纹状体病理学，这些数据提出了我们和其他人在 SN 神经元中发现的高水平体细胞 mtDNA 突变的可能性。 PD 可能导致 PD 中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，那么拟议的关于运动对体细胞 mtDNA 突变和 PGC-1 的影响的研究。该项目的主要目标是研究体育锻炼对 Polg 突变小鼠大脑的保护作用的潜在机制，包括对体细胞 mtDNA 突变水平和 PGC 调节的影响。 -1¿这种有针对性的方法将得到公正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。公共健康相关性：体育锻炼可以改善线粒体功能并对大脑产生强大的保护作用，但这些作用的机制尚不清楚，了解这些机制可以为与衰老和帕金森病等与年龄相关的神经退行性疾病相关的新型神经保护策略提供见解。我们现在建议通过研究过早衰老的小鼠模型来研究运动对大脑的保护机制。