Treadmill Exercise Attenuates α-Synuclein Levels by Promoting Mitochondrial Function and Autophagy Possibly via SIRT1 in the Chronic MPTP/P-Induced Mouse Model of Parkinson's Disease
Treadmill Exercise Attenuates α-Synuclein Levels by Promoting Mitochondrial Function and Autophagy Possibly via SIRT1 in the Chronic MPTP/P-Induced Mouse Model of Parkinson's Disease
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DOI：
10.1007/s12640-017-9770-5
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发表时间：
2017-10-01
影响因子：
3.7
通讯作者：
Cho, Joon-Yong
中科院分区：
文献类型：
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作者：
Koo, Jung-Hoon;Cho, Joon-Yong
α-突触核蛋白（α-Syn）的积累与帕金森病（PD）的主要症状-进行性运动缺陷的存在显著相关。虽然体育锻炼会降低α-Syn水平，但体育锻炼降低α-Syn的分子机制仍不清楚。我们假设，在慢性1-甲基-1，2，3，6-四氢吡啶联合丙磺舒（MPTP/P）诱导的PD小鼠模型中，跑步机运动（TE）通过改善线粒体功能和促进自噬（经由sirtuin-1（SIRT1）信号通路）来降低alpha-Syn水平。我们发现TE降低了α-Syn水平，随后改善了多巴胺能（DA能）神经元损失和α-Syn介导的凋亡性细胞死亡。最重要的是，TE增加SIRT1表达，从而通过激活过氧化物酶体增殖物激活受体γ共激活因子-1 α（PGC-1 α）增加线粒体生物合成并降低氧化应激。TE激活SIRT1还通过诱导微管相关蛋白1轻链3（LC 3）的激活促进自噬清除α-Syn。总的来说，我们的研究结果表明，TE可以通过改善线粒体功能和增加自噬通量来降低α-Syn水平，从而改善PD小鼠中慢性MPTP/P诱导的运动缺陷。
Accumulation of alpha-synuclein (alpha-Syn) is significantly correlated with the presence of progressive motor deficits, which is the main symptom of Parkinson's disease (PD). Although physical exercise reduces alpha-Syn levels, the molecular mechanisms by which physical exercise decreases alpha-Syn remain unclear. We hypothesized that treadmill exercise (TE) decreases alpha-Syn levels by improving mitochondrial function and promoting autophagy via the sirtuin-1 (SIRT1) signaling pathway in the chronic 1-methyl-1,2,3,6-tetrahydropyridine with probenecid (MPTP/P)-induced mouse model of PD. We found that TE reduces alpha-Syn levels, which subsequently ameliorates dopaminergic (DAergic) neuron loss and alpha-Syn-mediated apoptotic cell death. Most importantly, TE increases SIRT1 expression, which results in increased mitochondrial biogenesis and decreased oxidative stress by activating peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1 alpha). SIRT1 activation by TE also promotes autophagic clearance of alpha-Syn by inducing the activation of microtubule-associated protein 1 light chain 3 (LC3). Collectively, our results demonstrate that TE may reduce alpha-Syn levels by improving mitochondrial function and increasing autophagic flux, thereby ameliorating chronic MPTP/P-induced motor deficits in PD mice.