Helmholtz Zentrum München, Institute of Developmental Genetics, Ingolstädter Landstr. 1, 85764 Neuherberg, Germany.
Neurochem Int. 2013 Apr;62(5):738-49. doi: 10.1016/j.neuint.2013.01.010. Epub 2013 Jan 18.
Oxidative stress is a major common hallmark of many neurodegenerative disease such as Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and stroke. Novel concepts in our understanding of oxidative stress indicate that a perturbed redox circuitry could be strongly linked with the onset of such diseases. In this respect, glutathione and thioredoxin dependent antioxidant enzymes play a central role as key regulators due to the fact that a slight dysfunction of any of these enzymes leads to sustained reactive oxygen species (ROS) production. Apart from their classical role as ROS scavengers, some of these enzymes are also able to control post-translational modifications. Therefore, efficient control of ROS production and reversibility of post-translational modifications are critical as improper control of such events may lead to the activation of pathological redox circuits that eventually culminate in neuronal cell death. To dissect the apparently opposing functions of ROS in cell physiology and pathophysiology, a proper working toolkit is mandatory. In vivo modeling is an absolute requirement due to the complexity of redox signaling systems that often contradict data obtained from in vitro approaches. Hence, inducible/conditional knockout mouse models for key redox enzymes are emerging as powerful tools to perturb redox circuitries in a temporal and spatial manner. In this review we address the basics of ROS generation, chemistry and detoxification as well as examples in where applications of mouse models of important enzymes have been successfully applied in the study of neurodegenerative processes. We also highlight the importance of new models to overcome present technical limitations in order to advance in the study of redox processes in the role of neurodegeneration.
氧化应激是许多神经退行性疾病（如阿尔茨海默病、帕金森病、肌萎缩侧索硬化症和中风）的主要共同特征。我们对氧化应激的理解的新概念表明，失调的氧化还原电路可能与这些疾病的发生密切相关。在这方面，谷胱甘肽和硫氧还蛋白依赖的抗氧化酶作为关键调节剂发挥着核心作用，因为这些酶中的任何一种功能稍有失调都会导致持续的活性氧（ROS）产生。除了作为 ROS 清除剂的经典作用外，这些酶中的一些还能够控制翻译后修饰。因此，有效控制 ROS 产生和翻译后修饰的可逆性至关重要，因为这些事件的控制不当可能导致病理氧化还原电路的激活，最终导致神经元细胞死亡。为了剖析 ROS 在细胞生理学和病理生理学中看似对立的功能，需要一个适当的工作工具包。由于氧化还原信号系统的复杂性，体内建模是绝对必要的，因为这些系统的复杂性经常与体外方法获得的数据相矛盾。因此，针对关键氧化还原酶的诱导/条件性敲除小鼠模型正成为一种强大的工具，可在时间和空间上干扰氧化还原电路。在这篇综述中，我们讨论了 ROS 的生成、化学和解毒的基础知识，以及在这些方面应用重要酶的小鼠模型在神经退行性过程研究中的成功案例。我们还强调了新模型的重要性，以克服当前的技术限制，从而推进氧化还原过程在神经退行性变中的作用研究。
