Social Interaction in Neuroprotection and Lifespan of Drosophila SOD Mutants

描述(申请人提供)：我们在果蝇中发现了一种显著的，强大的社会互动延长寿命的效果，在铜/锌超氧化物歧化酶(SOD)缺陷的果蝇Sod突变中。缺乏超氧化物歧化酶活性阻碍了动物清除有氧代谢过程中产生的有害活性氧物种(ROS)的能力，导致加速衰老和过度应激反应，并与多种神经退行性疾病有关。我们发现，当与更年轻或更活跃的果蝇共居时，SOD突变体不仅显示出双倍的寿命，而且还提高了抗应激能力和运动协调性。这些表型为干预和解开相互作用的遗传网络和代谢途径提供了一个敏感的系统，这些遗传网络和代谢途径是某些神经保护机制和寿命决定的基础。我们将采用多学科的方法，利用我们实验室和合作者开发的分子、遗传、生理和行为工具来促进关联 在同一个体或同一组苍蝇中接受不同水平的研究。目的：改进行为学实验，揭示有益行为相互作用的本质，为进一步了解草蝇社会交往的神经保护作用奠定基础。我们的目标是将我们实验室新开发的自动视频跟踪系统IowaFLI Tracker与其他标准行为技术结合使用。目的：有或没有共居助手的草蝇将通过qRT-PCR和Western Blot分析关键的氧化还原酶或其底物，以揭示它们在助手效应中的潜在作用，这是因为它们在这一神经保护过程中对ROS代谢的代偿调节。此外，大量现存的控制膜兴奋性和代谢途径的基因之间的双突变将有助于构建一个连接代谢途径和由超氧化物歧化酶功能产生的神经元兴奋性调控的相互作用图谱。通过微阵列分析，可能会发现突出反应基因缺失的环节和新的分支。目的：改善运动协调性和抗应激能力的有益效果将进一步与与帮助者共居的草皮蝇衰老过程中神经元和神经回路的生理改变相关。我们将确定具有弹性的生理参数以及容易发生超氧化物歧化酶突变扰动的不稳定属性。这将以具体的生理术语定义神经系统老化的里程碑，这些里程碑对社会互动的神经保护作用做出反应。

DESCRIPTION (provided by applicant): We found a striking, robust life-span extension effect of social interaction in Drosophila Sod mutants defective in Cu/Zn superoxide dismutase (SOD). Lacking SOD enzymatic activity hampers the ability of animals to clear the harmful reactive oxygen species (ROS) generated in aerobic metabolic process, leading to accelerated aging and excessive stress responses, and is implicated in several neurodegenerative diseases. We found that upon co-housing with younger or more active flies, Sod mutants display not only a doubled lifespan, but also improved stress-resistance and motor coordination. These phenotypes provide a sensitized system for intervention and for unraveling the interacting genetic networks and metabolic pathways underlying certain neuroprotective mechanisms and lifespan determination. We will adopt a multi-disciplinary approach with the molecular, genetic, physiological and behavioral tools developed in our lab and collaborators to facilitate correlation within the same individual or groups of flies subjected to studies at different levels. Aim1: To refine the behavioral experiments to reveal the nature of beneficial behavioral interactions for further understanding of the neuroprotective effect of social interaction in Sod flies. We aim to use the automated video tracking system, IowaFLI Tracker, newly developed in our lab in conjunction with other standard behavioral techniques. Aim2: Sod flies with or without co-housed helpers will be examined for key redox enzymes or their substrates by qRT-PCR and Western Blot analysis to uncover their potential roles in the helper effect, as suggested by their compensatory adjustments in ROS metabolism in this neuroprotective process. In addition a large extant collection of double mutants among genes controlling membrane excitability and metabolic pathways will facilitate construction of an interaction map linking metabolic pathways and neuronal excitability control emanating from Sod function. Missing links and new branches from prominent responder genes may emerge through a microarray analysis. Aim3: The beneficial effects of improved motor coordination and stress resistance will be further correlated with physiological modifications in neurons and neural circuits during aging of Sod flies co-housed with helpers. We will identify resilient physiological parameters as well as labile properties that are prone to Sod mutational perturbations. This will define in concrete physiological terms the landmarks of nervous system aging that are responsive to neuroprotective effect of social interactions.