Plasmalogens rescue neuronal cell death through an activation of AKT and ERK survival signaling.
Plasmalogens rescue neuronal cell death through an activation of AKT and ERK survival signaling.
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DOI：
10.1371/journal.pone.0083508
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Katafuchi T
中科院分区：
文献类型：
--
作者：
Hossain MS;Ifuku M;Take S;Kawamura J;Miake K;Katafuchi T
神经元细胞对多种应激反应敏感，从而导致细胞凋亡和神经退行性疾病。神经元保护免受这些凋亡刺激的精确分子机制对于药物发现是必要的。在本研究中，我们发现，缩醛磷脂（Pls），这是甘油磷脂含有乙烯基醚连接在sn-1的位置，可以保护神经细胞的死亡后，血清剥夺。有趣的是，caspase-9，而不是caspase-8和caspase-12，在Neuro-2A细胞中的血清饥饿时被切割。Pls处理有效地降低了caspase-9的活化。此外，细胞信号实验表明，磷脂酰肌醇3-激酶（PI 3 K）依赖性丝氨酸/苏氨酸特异性蛋白激酶AKT和细胞外信号调节激酶ERK 1/2的磷酸化增强。PI 3 K/AKT抑制剂LY 294002和MAPK/ERK激酶（MEK）抑制剂U 0126处理研究清楚地表明，Pls介导的细胞存活依赖于这些激酶的激活。此外，Pls还抑制由营养剥夺诱导的原代小鼠海马神经元细胞死亡，这与抑制caspase-9和caspase-3裂解有关。有研究表明，阿尔茨海默病患者脑内磷脂酰肌醇含量降低，提示磷脂酰肌醇含量的降低可能危及神经元。本研究结果表明，磷脂在脑中具有抗凋亡作用。进一步研究Pls介导的抗细胞死亡的确切机制可能会导致我们建立一种新的治疗方法来治疗神经退行性疾病。
Neuronal cells are susceptible to many stresses, which will cause the apoptosis and neurodegenerative diseases. The precise molecular mechanism behind the neuronal protection against these apoptotic stimuli is necessary for drug discovery. In the present study, we have found that plasmalogens (Pls), which are glycerophospholipids containing vinyl ether linkage at sn-1 position, can protect the neuronal cell death upon serum deprivation. Interestingly, caspse-9, but not caspase-8 and caspase-12, was cleaved upon the serum starvation in Neuro-2A cells. Pls treatments effectively reduced the activation of caspase-9. Furthermore, cellular signaling experiments showed that Pls enhanced phosphorylation of the phosphoinositide 3-kinase (PI3K)-dependent serine/threonine-specific protein kinase AKT and extracellular-signal-regulated kinases ERK1/2. PI3K/AKT inhibitor LY294002 and MAPK/ERK kinase (MEK) inhibitor U0126 treatments study clearly indicated that Pls-mediated cell survival was dependent on the activation of these kinases. In addition, Pls also inhibited primary mouse hippocampal neuronal cell death induced by nutrient deprivation, which was associated with the inhibition of caspase-9 and caspase-3 cleavages. It was reported that Pls content decreased in the brain of the Alzheimer’s patients, which indicated that the reduction of Pls content could endanger neurons. The present findings, taken together, suggest that Pls have an anti-apoptotic action in the brain. Further studies on precise mechanisms of Pls-mediated protection against cell death may lead us to establish a novel therapeutic approach to cure neurodegenerative disorders.
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影响因子：
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通讯作者：
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影响因子：
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