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: 7312781
• 负责人: ATANU DUTTAROY
• 金额: $ 19.31万
• 依托单位: HOWARD UNIVERSITY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7312781
• 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，在肌萎缩侧索硬化症（ALS）患者中观察到 Cu-ZnSOD 活性降低和相关的神经病理学，在表达突变 Cu-ZnSOD 肽的小鼠中出现类似 ALS 的表型，以及在 MnSOD 敲除的情况下报告的极端神经病理学老鼠强烈支持这个观点。然而，可以说观察到的神经肌肉病理学是最终表型效应，其主要不是由于 SOD 活性降低而产生的。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体的线粒体中普遍存在，线粒体 SOD 活性缺乏会缩短所有研究生物体的寿命，这一事实证明了这一点。我们假设 MnSOD 活性降低会在较早的年龄引发神经肌肉变性，并且这种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逐渐降低相关，这可能是由于这些果蝇遭受的大量神经元损失所致。 MnSOD 无效 (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、神经变性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) 寿命短可以更快地分析随年龄变化的进行性退化事件； (3) MnSOD 的转基因过表达将用于挽救任何观察到的病理。该研究将为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随年龄变化的神经肌肉能力和认知提供有价值的信息。