Neuronal death in cultured murine cortical cells is induced by inhibition of GAPDH and triosephosphate isomerase.
Neuronal death in cultured murine cortical cells is induced by inhibition of GAPDH and triosephosphate isomerase.
复制标题
培养的小鼠皮质细胞中的神经元死亡是通过抑制 GAPDH 和磷酸丙糖异构酶来诱导的。
DOI：
10.1006/nbdi.1998.0177
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发表时间：
1998
期刊：
影响因子：
--
通讯作者：
Choi,DW
中科院分区：
文献类型：
--
作者：
Sheline,CT;Choi,DW
在CAG重复疾病亨廷顿病和齿状核红核苍白球路易氏体萎缩中表达的含聚谷氨酰胺的蛋白质最近被认为抑制关键糖酵解酶甘油醛-3-磷酸脱氢酶（GAPDH）。为了检测GAPDH抑制对神经元存活的影响，我们将小鼠新皮层细胞培养物暴露于GAPDH和磷酸丙糖异构酶的抑制剂α-单氯乙醇。培养物暴露于6-15 mM α-单氯乙醇48 h后，磷酸二羟丙酮增加，神经元ATP减少，随后发生进行性神经元死亡;一些神经胶质细胞死亡发生在高药物浓度下。神经元死亡的特点是细胞体收缩和染色质凝聚，是敏感的放线菌酮和半胱天冬酶抑制剂Z-Val-Ala-Asp氟甲基酮和叔丁氧羰基-Asp氟甲基酮。纹状体细胞培养物中的神经元更容易受到暴露于α-单氯醇诱导的死亡，除了NADPH-黄递酶（+）神经元被选择性地保留。反复添加糖酵解终点代谢产物丙酮酸盐到浴液中减弱了神经元ATP的下降和神经元细胞死亡。
Polyglutamine-containing proteins expressed in the CAG repeat diseases Huntington's disease and dentatorubralpallidoluyisian atrophy have recently been suggested to inhibit the key glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH). To examine the consequences of GAPDH inhibition upon neuronal survival, we exposed murine neocortical cell cultures to the inhibitor of GAPDH and triosephosphate isomerase, α-monochlorohydrin. Cultures exposed to 6–15 mM α-monochlorohydrin for 48 h exhibited an increase in dihydroxyacetone phosphate and a decrease in neuronal ATP that was followed by progressive neuronal death; some glial death occurred at high drug concentrations. The neuronal death was characterized by cell body shrinkage and chromatin condensation and was sensitive to cycloheximide and to the caspase inhibitors Z-Val-Ala-Asp fluoromethylketone and tert-butoxycarbonyl-Asp fluoromethylketone. Neurons in striatal cell cultures were more vulnerable to death induced by exposure to α-monochlorohydrin, except that NADPH-diaphorase(+) neurons were selectively spared. Repeated addition of the glycolytic endpoint metabolite pyruvate to the bathing medium attenuated both the drop in neuronal ATP and the neuronal cell death.