Mitochondrial dysfunction in Parkinson's disease
Mitochondrial dysfunction in Parkinson's disease
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DOI：
10.1042/bss0660085
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发表时间：
1999-01-01
期刊：
影响因子：
--
通讯作者：
Stephans, SE
中科院分区：
文献类型：
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作者：
Greenamyre, JT;MacKenzie, G;Stephans, SE
帕金森病（PD）的原因是未知的，但减少活动的电子传递链的复合物I已牵连在线粒体通透性转换孔诱导的帕金森综合征和特发性PD的发病机制。我们开发了一种新的PD模型，其中慢性全身输注鱼藤酮（一种复合物I抑制剂）选择性地杀死多巴胺能神经末梢，并在数月内导致黑质神经元退行性变性。多巴胺能病理学的分布复制了PD中所见，并且神经变性的缓慢时间过程比当前模型更准确地模拟PD。我们的模型应该加强我们对PD神经退行性变的理解。代谢障碍消耗ATP，抑制Na+/K+-ATP酶活性，并引起分级的神经元去极化。这缓解了谷氨酸受体的N-甲基-D-天冬氨酸（NMDA）亚型的电压依赖性Mg 2+阻滞，该受体对Ca 2+具有高度渗透性。因此，无害水平的谷氨酸通过继发性兴奋性毒性变得致命。线粒体损伤也破坏细胞Ca 2+稳态。此外，NMDA受体功能的促进导致进一步的线粒体功能障碍。在很大程度上，这是因为通过NMDA受体进入神经元的Ca 2+具有“特权”进入线粒体，在那里它引起自由基的产生和线粒体去极化。因此，可能存在前馈循环，其中线粒体功能障碍引起NMDA受体活化，这导致进一步的线粒体损伤。在这种情况下，NMDA受体拮抗剂可能具有神经保护作用。
The cause of Parkinson's disease (PD) is unknown, but reduced activity of complex I of the electron-transport chain has been implicated in the pathogenesis of both mitochondrial permability transition pore-induced Parkinsonism and idiopathic PD. We developed a novel model of PD in which chronic, systemic infusion of rotenone, a complex-I inhibitor, selectively kills dopaminergic nerve terminals and causes retrograde degeneration of substantia nigra neurons over a period of months. The distribution of dopaminergic pathology replicates that seen in PD, and the slow time course of neurodegeneration mimics PD more accurately than current models. Our model should enhance our understanding of neurodegeneration in PD. Metabolic impairment depletes ATP, depresses Na+/K+-ATPase activity, and causes graded neuronal depolarization. This relieves the voltage-dependent Mg2+ block of the N-methyl-D-aspartate (NMDA) subtype of the glutamate receptor, which is highly permeable to Ca2+ Consequently, innocuous levels of glutamate become lethal via secondary excitotoxicity. Mitochondrial impairment also disrupts cellular Ca2+ homoeostasis. Moreover, the facilitation of NMDA-receptor function leads to further mitochondrial dysfunction. To a large part, this occurs because Ca2+ entering neurons through NMDA receptors has 'privileged' access to mitochondria, where it causes free-radical production and mitochondrial depolarization. Thus there may be a feed-forward cycle wherein mitochondrial dysfunction causes NMDA-receptor activation, which leads to further mitochondrial impairment. In this scenario, NMDA-receptor antagonists may be neuroprotective.