Manganese Superoxide Dismutase in Mechanisms of Aging and Neurodgeneration

许多证据表明，细胞超氧化物歧化酶（SOD）活性与神经系统完整性的维持有关。例如，在肌萎缩性侧索硬化症（ALS）患者中可以看到Cu-ZnSOD活性降低和相关的神经病变，在表达突变Cu-ZnSOD肽的小鼠中出现ALS样表型，在MnSOD敲除小鼠中报道的极端神经病变强烈支持这一观点。然而，可以认为观察到的神经肌肉病变是终末表型效应，并非主要由SOD活性降低引起。换句话说，氧化损伤和神经变性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，这一点从线粒体SOD活性缺乏会缩短所有生物的寿命这一事实中得到了证明。我们假设MnSOD活性的降低应该在更早的年龄引发神经肌肉变性，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设，因为MnSOD活性的降低与运动能力的进行性降低有关，可能是由于这些果蝇遭受了大量的神经元损失。MnSOD缺失基因（Sod2n283）和弱等位基因（Sod2WK）及其组合为研究氧化应激对神经肌肉能力、认知、神经变性的影响及其对自然衰老的影响提供了独特的模型。在这种情况下使用果蝇模型将是理想的，因为(1)神经病理和神经生理评估工具的广泛可用性；(2)较短的寿命可以更快地分析进行性变性事件作为年龄的函数；(3)利用转基因过表达MnSOD来挽救观察到的任何病理。该研究将为氧化损伤引起的神经变性以及它如何影响神经肌肉能力和认知能力提供有价值的信息，作为一个完整的动物模型的功能。

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.