Moderate chronic treadmill exercise slows dopaminergic neuron loss in a rat model of Parkinson's disease and alters RNA content of circulating plasma exosomes

Exercise has been reported to improve outcomes in patients with Parkinson’s disease, but the exact biological mechanisms remain incompletely understood. This study was conducted to determine whether chronic moderate treadmill exercise prevents dopaminergic neuron loss and Lewy body-like inclusion burden in a preclinical model of PD. This study also sought to identify plasma exosome bound “exerkinesâ€� with potential to induce neuroprotective brain adaptations. Benefits of exercise are thought to be achieved in part through nucleic acids, lipids, and peptides termed exerkines abundant during exercise. These exerkines can induce cell specific exercise adaptations culminating in neuroprotection. Membrane-free exerkines, are subject to degradation in blood and may not effectively cross the blood brain barrier to induce brain adaptations to exercise limiting their inter-organ signaling potential. This led us to hypothesize that exerkines, bioactive RNAs in particular, may be selectively packaged into exosomes and released into plasma during exercise. Exosomes are small extracellular vesicles, selectively packaged and released by cells, with likely important differences in composition at rest, during injury and disease, and in response to exercise. Exosomes have been demonstrated to play a major role in inter-organ communication. Chronic exercise was found to provide neuroprotection to dopaminergic neurons in the substantia nigra pars compacta, without affecting Lewy body-like inclusion burden in nigra or the striatum. Plasma exosomal RNA was isolated from age matched exercising and sedentary non-PD rats and sequenced. We report 27 unique RNAs upregulated in the exosomes of exercisers, 3 mRNAs with clear neuroprotective potential.已有研究表明，运动可改善帕金森病（Parkinson’s disease）患者的预后，但具体的生物学机制仍未完全阐明。本研究旨在探究慢性中等强度跑台运动，能否在帕金森病临床前模型中阻止多巴胺能神经元（dopaminergic neuron）丢失，并降低路易体样包涵体（Lewy body-like inclusion）负荷。此外，本研究还试图鉴定血浆外泌体（plasma exosome）结合的"运动因子（exerkines）"，这类因子或可诱导脑内产生神经保护性适应。 学界认为，运动的益处部分通过运动因子实现——这类物质富含核酸、脂质与肽类，在运动过程中大量富集，可诱导细胞产生特异性运动适应，最终实现神经保护作用。但无膜结构的运动因子易在血液中降解，且可能无法有效跨越血脑屏障（blood brain barrier）以诱导脑内产生运动适应，这限制了其器官间信号传导的潜力。基于此，我们提出假说：运动因子，尤其是其中具有生物活性的RNA，或可在运动过程中被选择性包装进入外泌体，并释放至血浆中。 外泌体是一类由细胞选择性包装并释放的小型细胞外囊泡（extracellular vesicles），在静息状态、损伤与疾病状态下，以及运动应答过程中，其组成可能存在显著差异。已有研究证实，外泌体在器官间通讯中发挥关键作用。 本研究发现，慢性运动可对黑质致密部（substantia nigra pars compacta）的多巴胺能神经元产生神经保护作用，但未影响黑质与纹状体（striatum）内的路易体样包涵体负荷。我们从年龄匹配的运动组与久坐组非帕金森病大鼠体内分离血浆外泌体RNA并进行测序。研究结果显示，运动组大鼠外泌体中共存在27种上调的特异性RNA，其中3种信使RNA（mRNA）具有明确的神经保护潜力。