Manganese Superoxide Dismutase in Mechanisms of Aging

现在有许多证据表明，细胞中的超氧化物歧化酶(SOD)活性与维持神经系统的完整性有关。例如，在肌萎缩侧索硬化症(ALS)患者中可以看到铜-锌超氧化物歧化酶活性降低和相关的神经病理学，在表达突变的铜-锌超氧化物歧化酶多肽的小鼠中出现类似肌萎缩侧索硬化症的表型，在MnSOD基因敲除小鼠中报道的极端神经病理学强烈支持这一观点。然而，可以争辩说，所观察到的神经肌肉病理是终末表型效应，主要不是由于SOD活性降低而引起的。换句话说，氧化损伤和神经退行性变之间的关键联系仍然难以捉摸。氧化损伤保护系统在所有需氧生物的线粒体中都是必不可少的，这从线粒体SOD活性的缺乏会降低所有所研究的生物的寿命这一事实中可见一斑。我们假设，MnSOD活性降低应该在较早的年龄启动神经肌肉变性，并且变性本质上应该是进行性的。我们的初步结果支持这一假说，因为MnSOD活性的降低与运动能力的进行性降低有关，推测是由于这些果蝇遭受的大量神经元丢失所致。MnSOD缺失(Sod2n283)和弱等位基因(Sod2WK)及其组合为我们提供了一个独特的模型来研究氧化应激对神经肌肉能力、认知、神经退变的影响，以及它是如何影响自然衰老的。在这种情况下使用果蝇模型将是理想的，因为(1)神经病理学和神经生理学评估的工具广泛可用；(2)短的寿命允许更快地分析作为年龄函数的进行性退化事件；(3)转基因过表达MnSOD将被用来挽救任何观察到的病理。这项研究将提供关于氧化损伤引起的神经退行性变以及它如何影响整个动物模型中作为年龄函数的神经肌肉能力和认知的有价值的信息。

Many pieces of evidence now demonstrate that cellular superoxide dismutase (SOD) activities are associated with the maintenance of the integrity of the nervous system. For example, reduced Cu-ZnSOD activity and associated neuropathologies are seen in Amyotrophic Lateral Sclerosis (ALS) patients, an ALS-like phenotype appears in mice expressing the mutant Cu-ZnSOD peptde, and the extreme neuropathologies reported in the case of MnSOD knock out mice strongly support this notion. However, it can be argued that the observed neuromuscular pathologies are terminal phenotypic effects that did not arise primarily due to reduced SOD activity. In other words, the critical connection between oxidative damage and neurodegeneration remains elusive. An oxidative damage protection system is essential ubiquitously in the mitochondria of all aerobic organisms, as evident from the fact that lack of mitochondrial SOD activity reduces the life span in all organisms studied. We hypothesize that reduced MnSOD activity should initiate neuromuscular degeneration at an earlier age and that degeneration ought to be progressive in nature. Our preliminary results support this hypothesis since reduction in MnSOD activity is associated with progressive reduction in motor ability, presumably due to the massive neuronal loss that these flies suffer. A MnSOD null (Sod2n283) and a weak allele (Sod2WK) and their combinations provide us with a unique model to study the effects of oxidative stress on neuromuscular ability, cognition, neurodegeneration, and how it influences natural aging. Using the Drosophila model in this context will be ideal because of the (1) broad availability of tools for neuropathological and neurophysiological assessments; (2) the short life span allows faster analysis of progressive degeneration events as a function of age; and (3) transgenic overexpression of MnSOD will be employed to rescue any observed pathologies. The study will provide valuable information on oxidative damage induced neurodegeneration as well as how it influences the neuromuscular ability and cognition as a function of age in a whole animal model.