Cookson M R, Shaw P J
Department of Neurology, University of Newcastle upon Tyne, UK.
Brain Pathol. 1999 Jan;9(1):165-86. doi: 10.1111/j.1750-3639.1999.tb00217.x.
The effects of oxidative stress within post mitotic cells such as neurones may be cumulative, and injury by free radical species is a major potential cause of the age-related deterioration in neuronal function seen in several neurodegenerative diseases. There is strong evidence that oxidative stress plays an important role in the pathogenesis of motor neurone disease (MND). Point mutations in the antioxidant enzyme Cu,Zn superoxide dismutase (SOD1) are found in some pedigrees with the familial form of MND. How mutations in this ubiquitous enzyme cause the relatively selective cell death of specific groups of motor neurones is not clear, although a number of hypotheses have been forwarded. These include (1) the formation of hydroxyl radicals, (2) the catalysis of reactions of the nitrogen centred oxidant species peroxynitrite, (3) toxicity of copper or zinc and (4) protein aggregation. Some experimental support for these different hypotheses has been produced by manipulating cells in culture to express the mutant SOD1 proteins and by generating transgenic mice which over-express mutant SOD1. Observations in these model systems are, in some cases at least, supported by observations made on pathological material from patients with similar SOD1 mutations. Furthermore, there are reports of evidence of free radical mediated damage to neurones in the sporadic form of MND. Several lines of evidence suggest that alterations in the glutamatergic neurotransmitter system may also play a key role in the injury to motor neurones in sporadic MND. There are several important subcellular targets, which may be preferentially impaired within motor neurones, including neurofilament proteins and mitochondria. Future research will need to identify the aspects of the molecular and physiological phenotype of human motor neurones that makes them susceptible to degeneration in MND, and to identify those genetic and environmental factors which combine to cause this disease in individuals and in familial pedigrees.
有丝分裂后细胞（如神经元）内氧化应激的影响可能会累积，自由基造成的损伤是几种神经退行性疾病中与年龄相关的神经元功能衰退的一个主要潜在原因。有强有力的证据表明氧化应激在运动神经元病（MND）的发病机制中起重要作用。在一些家族性MND谱系中发现抗氧化酶铜锌超氧化物歧化酶（SOD1）存在点突变。尽管已经提出了一些假说，但这种普遍存在的酶中的突变如何导致特定运动神经元群体相对选择性的细胞死亡尚不清楚。这些假说包括：（1）羟基自由基的形成；（2）以氮为中心的氧化剂过氧亚硝酸盐反应的催化作用；（3）铜或锌的毒性；（4）蛋白质聚集。通过在培养细胞中表达突变型SOD1蛋白以及培育过度表达突变型SOD1的转基因小鼠，已经为这些不同假说提供了一些实验支持。至少在某些情况下，这些模型系统中的观察结果得到了对具有相似SOD1突变的患者病理材料观察结果的支持。此外，有报告称在散发性MND中也有自由基介导的神经元损伤的证据。几条证据表明，谷氨酸能神经递质系统的改变在散发性MND中对运动神经元的损伤中也可能起关键作用。有几个重要的亚细胞靶点，运动神经元内可能会优先受损，包括神经丝蛋白和线粒体。未来的研究需要确定人类运动神经元分子和生理表型中使其易患MND退化的方面，并确定那些共同导致个体和家族谱系中这种疾病的遗传和环境因素。
