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）活性与维持神经系统的完整性有关。例如，在肌萎缩性的侧面硬化症（ALS）患者中可以看到降低的Cu-ZNSOD活性和相关的神经病理学，在表达突变的Cu-Znsod PeptDE的小鼠中出现了类似ALS样的表型，以及在MNSSOD的情况下报道了MNSSOD敲除小鼠的强烈支持。但是，可以说，观察到的神经肌肉病理是末期表型作用，主要是由于SOD活性降低而产生的。换句话说，氧化损伤与神经退行性之间的关键联系仍然难以捉摸。在所有有氧生物的线粒体中，氧化损伤保护系统至关重要，这可以明显看出，缺乏线粒体SOD活性会降低所研究的所有生物的寿命。我们假设减少的MNSOD活性应在更早的年龄开始神经肌肉变性，并且这种变性本质上应该是渐进的。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进行性降低有关，这可能是由于这些苍蝇遭受的巨大神经元丧失。 MNSOD NULL（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，以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老化。在这种情况下，使用果蝇模型将是理想的选择，因为（1）广泛可用于神经病理和神经生理评估的工具； （2）寿命短，可以更快地分析渐进的变性事件随着年龄的函数； （3）将采用MNSOD的转基因过表达来挽救任何观察到的病理。该研究将提供有关氧化损伤诱导神经退行性的有价值的信息，以及它如何影响整个动物模型中的神经肌肉能力和认知与年龄的函数。