Kir6.1/K-ATP channel on astrocytes protects against dopaminergic neurodegeneration in the MPTP mouse model of Parkinson's disease via promoting mitophagy
Kir6.1/K-ATP channel on astrocytes protects against dopaminergic neurodegeneration in the MPTP mouse model of Parkinson's disease via promoting mitophagy
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星形胶质细胞上的 Kir6.1/K-ATP 通道通过促进线粒体自噬预防帕金森病 MPTP 小鼠模型中的多巴胺能神经变性
DOI：
10.1016/j.bbi.2019.07.009
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发表时间：
2019-10-01
影响因子：
15.1
通讯作者：
Hu, Gang
中科院分区：
文献类型：
--
作者：
Hu, Zhao-Li;Sun, Ting;Hu, Gang
ATP敏感性钾（K-ATP）通道将细胞代谢与细胞膜电位耦合，参与包括帕金森病（PD）在内的脑部疾病。Kir6.1是K-ATP通道的成孔亚基，在星形胶质细胞中表达显著，参与调节其功能。然而，星形胶质细胞Kir6.1/K-ATP通道在PD中的确切作用还没有得到很好的表征。本研究以星形胶质细胞Kir6.1基因敲除（KO）小鼠为研究对象，探讨星形胶质细胞Kir6.1/K-ATP通道对神经毒素1-甲基-4-苯基-1，2，3，6-四氢吡啶诱发的多巴胺（DA）神经元变性的影响。在这里，我们发现星形胶质细胞Kir6.1基因敲除小鼠表现出更多的DA神经元损失在黑质腹侧（SNc），纹状体多巴胺水平较低，和更严重的运动功能障碍比对照组。有趣的是，这伴随着体内SNc和体外星形胶质细胞中神经炎症增加和自噬水平降低。在机制上，星形胶质细胞Kir6.1 KO抑制线粒体自噬，这导致星形胶质细胞中受损线粒体的积累、活性氧的产生和神经炎症的增加。星形胶质细胞线粒体自噬的恢复挽救了星形胶质细胞Kir6.1消融对线粒体功能障碍、炎症和DA神经元死亡的有害影响。总之，我们的研究结果表明，星形胶质细胞Kir6.1/K-ATP通道通过促进线粒体自噬来保护PD中的DA神经变性，并且表明星形胶质细胞Kir6.1/K-ATP通道可能是PD的有希望的治疗靶点。
ATP-sensitive potassium (K-ATP) channels, coupling cell metabolism to cell membrane potential, are involved in brain diseases, including Parkinson's disease (PD). Kir6.1, a pore-forming subunit of K-ATP channel, is prominently expressed in astrocytes and participates in regulating its function. However, the precise role of astrocytic Kir6.1-contaning K-ATP channel (Kir6.1/K-ATP) in PD is not well characterized. In this study, astrocytic Kir6.1 knockout (KO) mice were used to examine the effect of astrocytic Kir6.1/K-ATP channel on dopaminergic (DA) neurodegeneration triggered by the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Here, we found that astrocytic Kir6.1 KO mice showed more DA neuron loss in substantia nigra compacta (SNc), lower level of dopamine in the striatum, and more severe motor dysfunction than controls. Interestingly, this companied by increased neuroinflammation and decreased autophagy level in SNc in vivo and astrocytes in vitro. Mechanistically, astrocytic Kir6.1 KO inhibited mitophagy which resulted in an increase in the accumulation of damaged mitochondria, production of reactive oxygen species and neuroinflammation in astrocytes. Restoration of astrocytic mitophagy rescued the deleterious effects of astrocytic Kir6.1 ablation on mitochondrial dysfunction, inflammation and DA neuron death. Collectively, our findings reveal that astrocytic Kir6.1/K-ATP channel protects against DA neurodegeneration in PD via promoting mitophagy and suggest that astrocytic Kir6.1/K-ATP channel may be a promising therapeutic target for PD.