Dysfunction of mitochondrial complex I and the proteasome:: interactions between two biochemical deficits in a cellular model of Parkinson's disease
Dysfunction of mitochondrial complex I and the proteasome:: interactions between two biochemical deficits in a cellular model of Parkinson's disease
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DOI：
10.1046/j.1471-4159.2003.01952.x
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发表时间：
2003-09-01
影响因子：
4.7
通讯作者：
Hirsch, EC
中科院分区：
文献类型：
--
作者：
Höglinger, GU;Carrard, G;Hirsch, EC
两个生化赤字已被描述在帕金森氏病的黑质，线粒体复合物I的活性降低和蛋白酶体活性降低。我们分析了这些缺陷之间的相互作用，在原代中脑文化。蛋白酶体抑制剂（环氧霉素，MG 132）加剧了复合物I抑制剂[鱼藤酮，1-甲基-4-苯基吡啶（MPP+）]和毒性多巴胺类似物6-羟基多巴胺的毒性，但不加剧线粒体复合物II-V或兴奋毒素抑制剂[N -甲基-d-天冬氨酸（NMDA），红藻氨酸盐]的毒性。鱼藤酮和MPP+通过三磷酸腺苷（ATP）耗竭增加自由基和降低蛋白酶体活性。6-羟多巴胺还增加自由基，但不影响ATP水平并增加蛋白酶体活性，推测是对氧化损伤的反应。蛋白酶体抑制增强了鱼藤酮，MPP+和6-羟基多巴胺的毒性，在这些浓度下，它们使自由基水平增加大于或等于基线以上40%，超过了蛋白酶体抑制降低的细胞解毒氧化蛋白的能力，并且还加剧了复合物I抑制引起的ATP消耗。因此，自由基清除和刺激ATP生产的葡萄糖补充保护对协同毒性。总之，蛋白酶体抑制增加了神经元对正常亚毒性水平的自由基的脆弱性，并放大了复合物I抑制后的能量消耗。
Two biochemical deficits have been described in the substantia nigra in Parkinson's disease, decreased activity of mitochondrial complex I and reduced proteasomal activity. We analysed interactions between these deficits in primary mesencephalic cultures. Proteasome inhibitors (epoxomicin, MG132) exacerbated the toxicity of complex I inhibitors [rotenone, 1-methyl-4-phenylpyridinium (MPP+ )] and of the toxic dopamine analogue 6-hydroxydopamine, but not of inhibitors of mitochondrial complex II-V or excitotoxins [N -methyl-d-aspartate (NMDA), kainate]. Rotenone and MPP+ increased free radicals and reduced proteasomal activity via adenosine triphosphate (ATP) depletion. 6-hydroxydopamine also increased free radicals, but did not affect ATP levels and increased proteasomal activity, presumably in response to oxidative damage. Proteasome inhibition potentiated the toxicity of rotenone, MPP+ and 6-hydroxydopamine at concentrations at which they increased free radical levels greater than or equal to 40% above baseline, exceeding the cellular capacity to detoxify oxidized proteins reduced by proteasome inhibition, and also exacerbated ATP depletion caused by complex I inhibition. Consistently, both free radical scavenging and stimulation of ATP production by glucose supplementation protected against the synergistic toxicity. In summary, proteasome inhibition increases neuronal vulnerability to normally subtoxic levels of free radicals and amplifies energy depletion following complex I inhibition.