HIF1α is necessary for exercise-induced neuroprotection while HIF2α is needed for dopaminergic neuron survival in the substantia nigra pars compacta.
HIF1α is necessary for exercise-induced neuroprotection while HIF2α is needed for dopaminergic neuron survival in the substantia nigra pars compacta.
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DOI：
10.1016/j.neuroscience.2015.03.015
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发表时间：
2015-06-04
期刊：
影响因子：
3.3
通讯作者：
Smeyne RJ
中科院分区：
文献类型：
--
作者：
Smeyne M;Sladen P;Jiao Y;Dragatsis I;Smeyne RJ
运动可以降低患神经系统疾病的风险，并提高细胞能量生产的效率。然而，过度剧烈的运动会产生氧化应激。适当的氧合对所有组织的健康至关重要，而细胞氧的严格调节对平衡大脑中的O2水平和氧化还原稳态至关重要。缺氧诱导因子（HIF）1α和HIF 2 α是受细胞氧浓度调节的转录因子，启动血管发育、氧化还原稳态和细胞周期控制的基因调节。HIF 1 α和HIF 2 α有助于重要的适应机制，当氧和ROS稳态变得不平衡时发生。已经表明，通过在缺氧事件之前暴露于应激物的预处理减少了否则将发生的损伤。以前，我们报道了三个月的运动保护SNpc DA神经元免受复合物I抑制引起的毒性。在这里，我们鉴定了SNpc中表达HIF 1 α和HIF 2 α的细胞，并表明跑步运动会导致SNpc DA神经元缺氧，并改变HIF 1 α和HIF 2 α的表达。在出生后神经元中携带条件性敲除Hif1α的小鼠中，我们观察到单独运动产生SNpc TH+ DA神经元损失。HIF 1 α的缺失也会消除运动诱导的神经保护作用。在出生后神经元中缺乏HIF 2 α的小鼠中，成年SNpc中TH+ DA神经元的数量减少，但三个月的运动挽救了这种损失。结论：HIF 1 α是运动性神经保护所必需的，HIF 1 α和HIF 2 α对成年SNpc DA神经元的存活和功能都是必需的。
Exercise reduces the risk of developing a number of neurological disorders and increases the efficiency of cellular energy production. However, overly strenuous exercise produces oxidative stress. Proper oxygenation is crucial for the health of all tissues, and tight regulation of cellular oxygen is critical to balance O2 levels and redox homeostasis in the brain. Hypoxia Inducible Factor (HIF)1α and HIF2α are transcription factors regulated by cellular oxygen concentration that initiate gene regulation of vascular development, redox homeostasis, and cell cycle control. HIF1α and HIF2α contribute to important adaptive mechanisms that occur when oxygen and ROS homeostasis become unbalanced. It has been shown that preconditioning by exposure to a stressor prior to a hypoxic event reduces damage that would otherwise occur. Previously we reported that three months of exercise protects SNpc DA neurons from toxicity caused by Complex I inhibition. Here, we identify the cells in the SNpc that express HIF1α and HIF2α and show that running exercise produces hypoxia in SNpc DA neurons, and alters the expression of HIF1α and HIF2α. In mice carrying a conditional knockout of Hif1α in postnatal neurons we observe that exercise alone produces SNpc TH+ DA neuron loss. Loss of HIF1α also abolishes exercise-induced neuroprotection. In mice lacking Hif2α in postnatal neurons, the number of TH+ DA neurons in the adult SNpc is diminished, but three months of exercise rescues this loss. We conclude that HIF1α is necessary for exercise-induced neuroprotection and both HIF1α and HIF2α are necessary for the survival and function of adult SNpc DA neurons.