Understanding cell death in Parkinson's disease
Understanding cell death in Parkinson's disease
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DOI：
10.1002/ana.410440712
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发表时间：
1998-09-01
影响因子：
11.2
通讯作者：
Olanow, CW
中科院分区：
文献类型：
--
作者：
Jenner, P;Olanow, CW
帕金森氏病（PD）的病因目前的概念表明遗传和环境影响的作用。PD中黑质细胞变性的各种潜在原因的共同点是氧化应激的参与。尸检分析显示铁水平增加，复合物I活性降低，还原型谷胱甘肽（GSH）水平降低。GSH水平的降低可能是导致细胞死亡的级联事件中特别重要的组成部分，因为它发生在PD的症状前阶段，并可能直接诱导黑质细胞变性或使神经元对毒素的作用敏感。有证据表明，氧化应激可能起源于神经胶质细胞，而不是在神经元中，神经胶质功能的改变可能是一个重要的贡献者发生在PD的病理过程。氧化损伤发生在PD的大脑中，如黑质中脂质过氧化和DNA损伤增加所示。蛋白质氧化增加也是明显的，但这发生在大脑的许多区域，并提出了一个更广泛的病理过程发生在PD的幽灵，其中黑质是特别脆弱的。黑质不能处理受损或突变的蛋白质（如α-突触核蛋白），可能导致其聚集和沉积，并形成路易体。事实上，路易体对α-突触核蛋白和硝化蛋白都染色。目前的证据使我们能够假设，在表现出氧化应激的大脑区域中未能处理结构修饰的蛋白质是家族性和散发性PD的原因。
Current concepts of the cause of Parkinson's disease (PD) suggest a role for both genetic and environmental influences. Common to a variety of potential causes of nigral cell degeneration in PD is the involvement of oxidative stress. Postmortem analysis shows increased levels of iron, decreased complex I activity, and a decrease in reduced glutathione (GSH) levels. The decrease in GSH levels may be a particularly important component of the cascade of events leading to cell death because it occurs in the presymptomatic stage of PD and may directly induce nigral cell degeneration or render neurons susceptible to the actions of toxins. There is evidence suggesting that oxidative stress might originate in glial cells rather than in neurons, and alterations in glial function may be an important contributor to the pathologic process that occurs in PD. Oxidative damage occurs in the brain in PD, as shown by increased lipid peroxidation and DNA damage in the substantia nigra. Increased protein oxidation is also apparent, but this occurs in many areas of the brain and raises the specter of a more widespread pathologic process occurring in PD to which the substantia nigra is particularly vulnerable. The inability of the substantia nigra to handle damaged or mutant (eg, alpha-synuclein) proteins may lead to their aggregation and deposition and to the formation of Lewy bodies. Indeed, Lewy bodies stain for both alpha-synuclein and nitrated proteins. Current evidence enables us to hypothesize that a failure to process structurally modified proteins in regions of the brain exhibiting oxidative stress is a cause of both familial and sporadic PD.