The roles of neuromelanin, binding of metal ions, and oxidative cytotoxicity in the pathogenesis of Parkinson's disease: a hypothesis.

W S Enochs, T Sarna, L Zecca, P A Riley, H M Swartz
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引用次数: 108

Abstract

A characteristic feature of both Parkinson's disease (idiopathic paralysis agitans) and normal aging is loss of pigmented neurons in the substantia nigra. This has been found to correlate with the accumulation of neuromelanin and with oxidative stress in this brain region, but a clear association between these factors has not been established. Based on our recent demonstration that neuromelanin is a true melanin, containing bound metal ions in situ, we present a general model for its accumulation in vivo and the hypotheses (1) that it has a cytoprotective function in the sequestration of redox-active metal ions under normal conditions but (2) that it has a cytotoxic role in the pathogenesis of Parkinson's disease. Thus, neuromelanin accumulates normally through the autooxidation of catecholamines and serves tightly to bind redox-active metal ions, processes which would accelerate under conditions of intracellular or extracellular oxidative stress. Based on the known properties of melanin, however, neuromelanin also has the potential for exacerbating oxidative stress, eg by generating H2O2 when it is intact or by releasing redox-active metal ions if it loses its integrity; these reactions also would modulate the reactivity of the neuromelanin. By overwhelming intracellular antioxidative defense mechanisms, such a positive-feedback cycle could turn a condition of chronic or repeated oxidative stress in vulnerable neurons into an acute crisis, leading to cellular death. If the cumulative stress in duration and/or degree is severe enough, neuronal depletion could be sufficient to cause Parkinson's disease during life. One possible trigger for this cascade is suggested by the increased nigral iron contents in postmortem parkinsonian brains and the correlation of this disease with urban living where exposure to heavy metal ions is high: the saturation of neuromelanin with redox-active metal ions. Parkinson's disease therefore may be a form of accelerated aging in the substantia nigra associated with environmental toxins in which neuromelanin has a central, active role.

神经黑色素、金属离子结合和氧化细胞毒性在帕金森病发病机制中的作用:一个假说。
帕金森病(特发性震颤性麻痹)和正常衰老的一个特征是黑质色素神经元的丢失。已经发现这与神经黑色素的积累和大脑该区域的氧化应激有关,但这些因素之间的明确联系尚未确定。基于我们最近的证明,神经黑色素是一种真正的黑色素,在原位含有结合的金属离子,我们提出了它在体内积累的一般模型和假设(1)它在正常条件下对氧化还原活性金属离子的隔离中具有细胞保护功能,但(2)它在帕金森病的发病机制中具有细胞毒性作用。因此,神经黑色素通常通过儿茶酚胺的自氧化积累,并紧密结合氧化活性金属离子,这一过程在细胞内或细胞外氧化应激条件下会加速。然而,根据黑色素的已知特性,神经黑色素也有可能加剧氧化应激,例如,当它完整时产生H2O2,或者当它失去完整性时释放氧化还原活性金属离子;这些反应也会调节神经黑色素的反应性。通过压倒细胞内抗氧化防御机制,这种正反馈循环可以将脆弱神经元的慢性或反复氧化应激状态转变为急性危机,导致细胞死亡。如果累积的压力在持续时间和/或程度上足够严重,神经元耗竭可能足以在一生中引起帕金森病。这种级联反应的一个可能的触发因素是死后帕金森大脑中黑质铁含量的增加,以及这种疾病与城市生活的相关性,在城市生活中重金属离子的暴露程度很高:神经黑色素与氧化还原活性金属离子的饱和。因此,帕金森病可能是与环境毒素相关的黑质加速衰老的一种形式,其中神经黑色素起着核心的积极作用。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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