Manganese Superoxide Dismutase in Mechanisms of Aging

锰超氧化物歧化酶在衰老机制中的作用

• 批准号: 6966942
• 负责人: ATANU DUTTAROY
• 金额: $ 20.52万
• 依托单位: HOWARD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6966942
• 关键词: Drosophilidae; aging; cell senescence; cognition; cooperative study; enzyme activity; gene mutation; manganese; mitochondria; neural degeneration; neuromuscular function; oxidative stress; pathologic process; superoxide dismutase

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.

现在有许多证据表明，细胞超氧化物歧化酶（SOD）活性与维持神经系统的完整性有关。例如，在肌萎缩性侧索硬化（ALS）患者中观察到降低的Cu-ZnSOD活性和相关的神经病理学，在表达突变Cu-ZnSOD肽的小鼠中出现ALS样表型，并且在MnSOD敲除小鼠的情况下报道的极端神经病理学强烈支持这一观点。然而，可以认为，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无处不在，从缺乏线粒体SOD活性降低所有研究生物的寿命这一事实中可以看出。我们推测，MnSOD活性降低应在较早的年龄开始神经肌肉变性，变性的性质应该是渐进的。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逐步降低有关，这可能是由于这些苍蝇遭受的大量神经元损失。MnSOD null（Sod 2n 283）和弱等位基因（Sod 2 WK）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，神经退行性变的影响，以及它如何影响自然衰老。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工具的广泛可用性;（2）短寿命允许更快地分析作为年龄函数的进行性变性事件;和（3）MnSOD的转基因过表达将用于挽救任何观察到的病理。这项研究将提供有价值的信息，氧化损伤诱导的神经变性，以及它如何影响神经肌肉能力和认知作为一个功能的年龄在整个动物模型。