Uncoupling protein 2 deficiency aggravates astrocytic endoplasmic reticulum stress and nod-like receptor protein 3 inflammasome activation
Uncoupling protein 2 deficiency aggravates astrocytic endoplasmic reticulum stress and nod-like receptor protein 3 inflammasome activation
复制标题
解偶联蛋白2缺乏加剧星形胶质细胞内质网应激和点头样受体蛋白3炎症小体激活
DOI：
10.1016/j.neurobiolaging.2013.08.015
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发表时间：
2014-02-01
影响因子：
4.2
通讯作者：
Hu, Gang
中科院分区：
文献类型：
--
作者：
Lu, Ming;Sun, Xiu-Lan;Hu, Gang
星形胶质细胞在决定大脑对氧化应激的易感性方面起着至关重要的作用，解偶联蛋白2(UCP2)已被证明调节活性氧(ROS)的产生。然而，目前还不清楚UCP2是否在星形胶质细胞中表达，以及它是否参与了星形胶质细胞功能的调节。在这里，我们发现UCP2基因敲除加剧了1，2，3，6-甲基-苯基-四氢吡啶(MPTP)诱导的帕金森病(PD)小鼠模型中多巴胺能神经元的丢失，并伴有星形胶质细胞的过度激活。我们进一步检测了UCP2在原代培养的中脑星形胶质细胞中的表达。在1-甲基-4-苯基吡啶(MPP+)处理下，UCP2基因敲除增加了细胞内ROS的产生，并诱导了氧化应激。随后，UCP2缺乏加重了内质网(ER)应激，表现为C/EBP同源蛋白(CHOP)上调，caspase-12裂解，并通过激活星形胶质细胞中的Nod样受体蛋白3(NLRP3)炎性小体而加重神经炎症。总之，我们的研究表明，UCP2在星形胶质细胞中表达，调节内质网应激和神经炎症，并在帕金森病发病机制中对多巴胺能神经元的生存至关重要。这些发现使我们深入了解UCP2作为PD治疗的一种新的治疗途径的潜力。(C)2014 Elsevier Inc.保留所有权利。
Astrocytes play crucial roles in determining the susceptibility to oxidative stress in the brain, and uncoupling protein 2 (UCP2) has been demonstrated to regulate reactive oxygen species (ROS) production. However, it is unclear whether UCP2 is expressed in astrocytes, and whether it participates in the regulation of astrocytic functions. Here we show that UCP2 knockout exacerbated dopaminergic neuron loss in a murine model of 1,2,3,6-methyl-phenyl-tetrahydropyridine (MPTP)-induced Parkinson's disease (PD), accompanied by overactivation of astrocytes. We further detected expression of UCP2 in primary cultures of mesencephalic astrocytes. UCP2 knockout increased intracellular ROS production and induced oxidative stress in response to 1-methyl-4-phenylpyridinium (MPP+) treatment. Subsequently, UCP2 deficiency exacerbated endoplasmic reticulum (ER) stress, as evidenced by the upregulations of C/EBP homologous protein (CHOP), cleavage of caspase-12, and aggravated neuroinflammation via the activation of nod-like receptor protein 3 (NLRP3) inflammasomes in astrocytes. Collectively, our study indicates that UCP2 expressed in astrocytes modulates ER stress and neuroinflammation, and is crucial for the survival of dopaminergic neuron in the pathogenesis of PD. These findings gives us insights into the potential of UCP2 as a novel therapeutic avenue for PD treatment. (C) 2014 Elsevier Inc. All rights reserved.