Involvement of glyceraldehyde-3-phosphate dehydrogenase in rotenone-induced cell apoptosis: Relevance to protein misfolding and aggregation
Involvement of glyceraldehyde-3-phosphate dehydrogenase in rotenone-induced cell apoptosis: Relevance to protein misfolding and aggregation
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3-磷酸甘油醛脱氢酶参与鱼藤酮诱导的细胞凋亡：与蛋白质错误折叠和聚集的相关性
DOI：
10.1016/j.brainres.2009.05.011
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发表时间：
2009-07-07
期刊：
影响因子：
2.9
通讯作者：
Wang, Tao
中科院分区：
文献类型：
--
作者：
Huang, Jinsha;Hao, Lijun;Wang, Tao
帕金森病（PD）的标志是黑质神经元（SNpc）中多巴胺能神经元的丢失和存活神经元中细胞内包涵体的存在。虽然散发性PD的具体病因和发病机制尚不清楚，但已证实神经元死亡与线粒体功能障碍和蛋白质错误折叠有关。然而，线粒体功能障碍和蛋白质错误折叠之间的分子联系仍然不清楚。甘油醛-3-磷酸脱氢酶（GAPDH）是一种典型的糖酵解酶，在正常情况下负责碳水化合物的代谢。当GAPDH易位至细胞核时，其在几种神经退行性疾病中促进神经元凋亡。但GAPDH易位似乎不是导致神经元凋亡的唯一机制。我们发现，鱼藤酮，一种常见的线粒体复合物I抑制剂，用于产生实验性帕金森病，不仅可以诱导GAPDH易位，但也触发分子间二硫键，并导致在胞浆内的GAPDH聚集体的形成。这表明线粒体功能障碍和蛋白质错误折叠之间存在联系，并揭示了帕金森病中路易体形成的病理生理学。(C)2009爱思唯尔有限公司版权所有。
The hallmarks of Parkinson's disease (PD) are the loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and the presence of intracellular inclusion bodies in surviving neurons. Although the specific etiology and pathogenesis of sporadic PD remains unknown, neuronal death was proven to be associated with mitochondrial dysfunction and protein misfolding. However, molecular links between mitochondrial dysfunction and protein misfolding remains obscure. Glyceraldehyde-3-phosphate dehydrogenase (GAPDH), a classical glycolytic enzyme, is responsible for carbohydrate metabolism under normal circumstances. When translocated to the nucleus, GAPDH promotes neuron apoptosis in several neurodegenerative disorders. But it seems that GAPDH translocation is not the sole mechanism responsible for neuronal apoptosis. We found that rotenone, a common mitochondrial complex I inhibitor used to produce experimental parkinsonism, cannot only induce GAPDH translocation but also trigger intermolecular disulfide bonding and result in the formation of intracytoplasmic aggregates of GAPDH. This suggests a link between mitochondrial dysfunction and protein misfolding, and sheds light on the pathophysiology of Lewy body formation in Parkinson's disease. (C) 2009 Elsevier B.V. All rights reserved.