A novel role for glyceraldehyde-3-phosphate dehydrogenase and monoamine oxidase B cascade in ethanol-induced cellular damage.
A novel role for glyceraldehyde-3-phosphate dehydrogenase and monoamine oxidase B cascade in ethanol-induced cellular damage.
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DOI：
10.1016/j.biopsych.2009.10.032
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发表时间：
2010-05-01
影响因子：
10.6
通讯作者：
Shih, Jean C.
中科院分区：
文献类型：
--
作者：
Ou, Xiao-Ming;Stockmeier, Craig A.;Meltzer, Herbert Y.;Overholser, James C.;Jurjus, George J.;Dieter, Lesa;Chen, Kevin;Lu, Deyin;Johnson, Chandra;Youdim, Moussa B. H.;Austin, Mark C.;Luo, Jia;Sawa, Akira;May, Warren;Shih, Jean C.
关键词：
酒精中毒是一种主要的精神疾病，至少部分与乙醇诱导的细胞损伤有关。虽然在酒精中毒的受试者中有脑细胞损失的报道，但分子机制尚不清楚。甘油醛-3-磷酸脱氢酶（GAPDH）和单胺氧化酶B（MAO B）据报道在应激条件下的细胞功能障碍中起作用，并可能导致乙醇诱导的细胞损伤。研究了暴露于生理浓度乙醇的人胶质母细胞瘤和神经母细胞瘤细胞系中GAPDH和MAO B蛋白的表达。这些蛋白质的表达也在前额叶皮层与酒精依赖的人类受试者和大鼠喂养的乙醇饮食。免疫共沉淀、亚细胞分级分离和荧光素酶测定用于解决核GAPDH介导的MAO B活化。为了测试失活的效果，使用RNAi和药物干预，并通过TUNEL和H2 O2测量来评估细胞损伤。乙醇显着增加神经元细胞以及人类和大鼠大脑中GAPDH（尤其是核GAPDH）和MAO B的水平。核GAPDH与转录激活因子转化生长因子β诱导型早期基因2（TIEG 2）相互作用，并增强TIEG 2介导的MAO B反式激活，这导致暴露于乙醇的神经元细胞的细胞损伤。GAPDH的敲低表达或用MAO B抑制剂司来吉兰（Deprenyl）和雷沙吉兰（Azilect）治疗可以阻断这种级联反应。乙醇引起的核GAPDH增强TIEG 2介导的MAO B，这可能在酒精中毒受试者的脑损伤中起作用。阻断这种级联反应的化合物是治疗策略的潜在候选者。
Alcoholism is a major psychiatric condition at least partly associated with ethanol-induced cell damage. Although brain cell loss has been reported in subjects with alcoholism, the molecular mechanism is unclear. Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and monoamine oxidase B (MAO B) reportedly play a role in cellular dysfunction under stressful conditions and may contribute to ethanol-induced cell damage. Expression of GAPDH and MAO B protein was studied in human glioblastoma and neuroblastoma cell lines exposed to physiological concentrations of ethanol. Expression of these proteins was also examined in the prefrontal cortex from human subjects with alcohol dependence and in rats fed with an ethanol diet. Co-immunoprecipitation, subcellular fractionation, and luciferase assay were used to address nuclear GAPDH-mediated MAO B activation. To test the effects of inactivation, RNAi and pharmacological intervention were used, and cell damage was assessed by TUNEL and H2O2 measurements. Ethanol significantly increases levels of GAPDH, especially nuclear GAPDH, and MAO B in neuronal cells as well as in human and rat brains. Nuclear GAPDH interacts with the transcriptional activator, transforming growth factor-beta-inducible early gene 2 (TIEG2), and augments TIEG2-mediated MAO B transactivation, which results in cell damage in neuronal cells exposed to ethanol. Knockdown expression of GAPDH or treatment with MAO B inhibitors selegiline (Deprenyl) and rasagiline (Azilect) can block this cascade. Ethanol-elicited nuclear GAPDH augments TIEG2-mediated MAO B, which may play a role in brain damage in subjects with alcoholism. Compounds that block this cascade are potential candidates for therapeutic strategies.
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