Glucose deprivation induces reticulum stress by the PERK pathway and caspase-7-and calpain-mediated caspase-12 activation
Glucose deprivation induces reticulum stress by the PERK pathway and caspase-7-and calpain-mediated caspase-12 activation
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DOI：
10.1007/s10495-013-0930-7
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发表时间：
2014-03-01
期刊：
影响因子：
7.2
通讯作者：
Massieu, Lourdes
中科院分区：
文献类型：
--
作者：
Garcia de la Cadena, Selene;Hernandez-Fonseca, Karla;Massieu, Lourdes
葡萄糖是大脑的主要能量来源，对于大脑的正常功能至关重要。 1型糖尿病患者如果超过胰岛素注射量，可能会出现严重的低血糖，如果不及时纠正，可能会导致急性脑损伤。导致低血糖脑损伤的机制尚不完全清楚，内质网（ER）应激的作用尚未研究。内质网中未折叠或错误折叠蛋白积累所导致的内质网应激可通过未折叠蛋白反应 (UPR) 来抵消。当UPR持续时，可能会发生细胞凋亡。我们检查了海马培养神经元葡萄糖剥夺 (GD) 期间 UPR 的激活及其在诱导细胞凋亡中的作用。观察到 UPR PERK 途径的激活，因为 GD 后 30 分钟发生 eIF2 α 磷酸化增加和转录因子 ATF4 水平升高，并且伴侣蛋白 GRP78 和转录因子 CHOP 的水平在 GD 2 小时后增加。此外，我们观察到 GD 期间 caspase-7 和 12 的早期激活，而 caspase-3 活性在葡萄糖重新引入期间仅短暂增加。抑制 caspase-3/7 和钙依赖性蛋白酶、钙蛋白酶，显着降低 caspase-12 活性。 ER 应激抑制剂 salubrinal 可防止神经元死亡和 caspase-12 活性。结果表明，UPR 的 PERK 通路通过激活 caspase-12 参与 GD 诱导的神经元凋亡，而不是线粒体依赖性 caspase 通路。此外，我们发现钙蛋白酶和 caspase-7 在 GD 后很快被激活，并介导 caspase-12 激活和神经元死亡。
Glucose is the main energy source in brain and it is critical for correct brain functioning. Type 1 diabetic patients might suffer from severe hypoglycemia if exceeding insulin administration, which can lead to acute brain injury if not opportunely corrected. The mechanisms leading to hypoglycemic brain damage are not completely understood and the role of endoplasmic reticulum (ER) stress has not been studied. ER stress resulting from the accumulation of unfolded or misfolded proteins in the ER is counteracted by the unfolded protein response (UPR). When the UPR is sustained, apoptotic death might take place. We have examined UPR activation during glucose deprivation (GD) in hippocampal cultured neurons and its role in the induction of apoptosis. Activation of the PERK pathway of the UPR was observed, as increased phosphorylation of eIF2 alpha and elevated levels of the transcription factor ATF4, occurred 30 min after GD and the levels of the chaperone protein, GRP78 and the transcription factor CHOP, increased after 2 h of GD. In addition, we observed an early activation of caspase-7 and 12 during GD, while caspase-3 activity increased only transiently during glucose reintroduction. Inhibition of caspase-3/7 and the calcium-dependent protease, calpain, significantly decreased caspase-12 activity. The ER stress inhibitor, salubrinal prevented neuronal death and caspase-12 activity. Results suggest that the PERK pathway of the UPR is involved in GD-induced apoptotic neuronal death through the activation of caspase-12, rather than the mitochondrial-dependent caspase pathway. In addition, we show that calpain and caspase-7 are soon activated after GD and mediate caspase-12 activation and neuronal death.