Origin and functional consequences of the complex I defect in Parkinson's disease
Origin and functional consequences of the complex I defect in Parkinson's disease
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DOI：
10.1002/ana.410400417
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发表时间：
1996-10-01
影响因子：
11.2
通讯作者：
Parker, WD
中科院分区：
文献类型：
--
作者：
Swerdlow, RH;Parks, JK;Parker, WD
线粒体电子传递酶NADH：泛醌氧化还原酶（复合物I），由线粒体DNA和核DNA编码，在帕金森病（PD）患者的多个组织中存在缺陷。这种病变的起源及其在PD神经变性中的作用尚不清楚。为了解决这些问题，我们创建了一个体外系统，在该系统中，可以系统地分析环境毒素、复合物I核DNA突变和线粒体DNA突变的潜在贡献。不含线粒体DNA的人神经母细胞瘤细胞的克隆系用来自PD或对照受试者的血小板的线粒体重新填充。培养5 - 6周后，测定这些胞质杂交细胞系的电子传递链活性、活性氧的产生以及对1-甲基-4-苯基吡啶鎓（MPP+）诱导凋亡细胞死亡的敏感性。在PD cybrids中，我们发现复合物I活性稳定下降20%，氧自由基产生增加，对1-甲基-4-苯基吡啶诱导的程序性细胞死亡的敏感性增加。PD中的复合物I缺陷似乎是遗传的，由线粒体DNA引起，并且可能通过促进活性氧产生和赋予增加的神经元对线粒体毒素的易感性在PD的神经变性中发挥重要作用。
The mitochondrial electron transport enzyme NADH:ubiquinone oxidoreductase (complex I), which is encoded by both mitochondrial DNA and nuclear DNA, is defective in multiple tissues in persons with Parkinson's disease (PD). The origin of this lesion and its role in the neurodegeneration of PD are unknown. To address these questions, we created an in vitro system in which the potential contributions of environmental toxins, complex I nuclear DNA mutations, and mitochondrial DNA mutations could be systematically analyzed. A clonal line of human neuroblastoma cells containing no mitochondrial DNA was repopulated with mitochondria derived from the platelets of PD or control subjects. After 5 to 6 weeks in culture, these cytoplasmic hybrid (cybrid) cell lines were assayed for electron transport chain activities, production of reactive oxygen species, and sensitivity to induction of apoptotic cell death by 1-methyl-4-phenyl pyridinium (MPP+). In PD cybrids we found a stable 20% decrement in complex I activity, increased oxygen radical production, and increased susceptibility to 1-methyl-4-phenyl pyridinium-induced programmed cell death. The complex I defect in PD appears to be genetic, arising from mitochondrial DNA, and may play an important role in the neurodegeneration of PD by fostering reactive oxygen species production and conferring increased neuronal susceptibility to mitochondrial toxins.