Department of Molecular Animal Physiology, Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen, The Netherlands.
Department of Cell Biology, Radboud University Medical Center, Nijmegen, The Netherlands.
Mol Neurobiol. 2018 Jul;55(7):5639-5657. doi: 10.1007/s12035-017-0775-0. Epub 2017 Oct 10.
Parkinson's disease (PD) is characterized by the degeneration of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc), resulting in motor and non-motor dysfunction. Physical exercise improves these symptoms in PD patients. To explore the molecular mechanisms underlying the beneficial effects of physical exercise, we exposed 1-methyl-4-phenyl-1,2,3,6-tetrahydropyrimidine (MPTP)-treated mice to a four-week physical exercise regimen, and subsequently explored their motor performance and the transcriptome of multiple PD-linked brain areas. MPTP reduced the number of DA neurons in the SNpc, whereas physical exercise improved beam walking, rotarod performance, and motor behavior in the open field. Further, enrichment analyses of the RNA-sequencing data revealed that in the MPTP-treated mice physical exercise predominantly modulated signaling cascades that are regulated by the top upstream regulators L-DOPA, RICTOR, CREB1, or bicuculline/dalfampridine, associated with movement disorders, mitochondrial dysfunction, and epilepsy-related processes. To elucidate the molecular pathways underlying these cascades, we integrated the proteins encoded by the exercise-induced differentially expressed mRNAs for each of the upstream regulators into a molecular landscape, for multiple key brain areas. Most notable was the opposite effect of physical exercise compared to previously reported effects of L-DOPA on the expression of mRNAs in the SN and the ventromedial striatum that are involved in-among other processes-circadian rhythm and signaling involving DA, neuropeptides, and endocannabinoids. Altogether, our findings suggest that physical exercise can improve motor function in PD and may, at the same time, counteract L-DOPA-mediated molecular mechanisms. Further, we hypothesize that physical exercise has the potential to improve non-motor symptoms of PD, some of which may be the result of (chronic) L-DOPA use.
帕金森病（PD）的特征是黑质致密部（SNpc）中的多巴胺能（DA）神经元退化，导致运动和非运动功能障碍。体育锻炼可改善 PD 患者的这些症状。为了探讨体育锻炼有益作用的分子机制，我们让 1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）处理的小鼠进行为期四周的体育锻炼方案，然后探索它们的运动表现和多个与 PD 相关的大脑区域的转录组。MPTP 减少了 SNpc 中的 DA 神经元数量，而体育锻炼改善了束棒行走、转棒和开放场中的运动行为。进一步，RNA-seq 数据的富集分析表明，在 MPTP 处理的小鼠中，体育锻炼主要调节了由 top 上游调节剂 L-DOPA、RICTOR、CREB1 或毒蕈碱/dalfampridine 调节的信号级联，与运动障碍、线粒体功能障碍和癫痫相关过程有关。为了阐明这些级联背后的分子途径，我们将每个上游调节剂诱导的差异表达 mRNA 编码的蛋白质整合到一个分子景观中，用于多个关键的大脑区域。最值得注意的是，与之前报道的 L-DOPA 对 SN 和腹侧纹状体中与昼夜节律和涉及 DA、神经肽和内源性大麻素的信号有关的 mRNA 表达的影响相反，体育锻炼有相反的效果。总之，我们的研究结果表明，体育锻炼可以改善 PD 的运动功能，同时可能对抗 L-DOPA 介导的分子机制。此外，我们假设体育锻炼有潜力改善 PD 的非运动症状，其中一些可能是（慢性）L-DOPA 使用的结果。
