S-Nitrosylation as a Modular of Gamma-Secretase Activity

描述（申请人提供）：阿尔茨海默病是一种严重的神经退行性疾病，表现残酷，治疗选择很少。尽管关于家族性阿尔茨海默病的发病机制已经有了很多发现，但对于导致这种影响约95%阿尔茨海默病患者的散发形式的疾病的机制知之甚少。具体来说，当直接参与这些事件的蛋白质发生突变时，环境和次级遗传线索是如何能够触发相同的病理生理事件的？在这个提议中，我假设氧化应激，特别是一氧化氮，可能会加剧甚至触发与家族性阿尔茨海默病中所见的淀粉样蛋白- β的过度产生。初步数据显示，负责β淀粉样蛋白生成的蛋白酶之一γ -分泌酶对一氧化氮诱导的s -亚硝基化很敏感，而一氧化氮能够增加γ -分泌酶的活性。这些结果表明，在许多促进散发性阿尔茨海默病的情况下，氧化应激如何直接增加淀粉样蛋白的产生，这是一个简单但强大的机制。为了进一步研究这种可能性，我提出了一系列的实验，这将有助于阐明和表征γ -分泌酶s -亚硝基化在淀粉样蛋白- β的整体生产中的作用。使用多种γ -分泌酶活性分析，这些实验将测试s -亚硝基化刺激γ -分泌酶活性的能力。此外，γ -分泌酶s -亚硝基化的具体机制将使用外源性和内源性一氧化氮来确定。如果这些实验结果表明-分泌酶s -亚硝基化在淀粉样蛋白的产生中起着重要作用，这将是阿尔茨海默氏症领域的重大发现。此外，它将对治疗甚至预防这种疾病的可能的新治疗方法产生重大影响。阿尔茨海默病是一种神经退行性疾病，影响着全球约2400万人。这一提议提出了一个关于什么可能引发阿尔茨海默病的新观点，表明阿尔茨海默病可能是由氧化应激增加引起的，氧化应激可能会改变疾病的一个重要因素。这项研究的结果可能会导致治疗阿尔茨海默病的新方法，包括新的、更具体的抗氧化治疗形式。

DESCRIPTION (provided by applicant): Alzheimer's disease is a serious neurodegenerative illness with a cruel manifestation and few treatment options. Although much has been uncovered about the pathogenesis of familial Alzheimer's disease, little is known about the mechanisms that bring about the sporadic form of the disease that affects about 95% of Alzheimer's patients. Specifically, how is it that environmental and secondary genetic cues are able to trigger the same pathophysiologic events that occur when the direct proteins involved in these events become mutated? In this proposal, I hypothesize that oxidative stress, and specifically nitric oxide, may be capable of exacerbating and perhaps even triggering the same overproduction of amyloid-beta that is seen in familial Alzheimer's disease. Preliminary data shows that gamma-secretase, one of the proteases responsible for amyloid-beta production, is susceptible to nitric oxide-induced S-nitrosylation, and that nitric oxide is capable of increasing gamma-secretase activity. These results suggests a simple but powerful mechanism for how the oxidative stress seen in many conditions that promote sporadic Alzheimer's disease may directly increase amyloid-beta production. In order to further investigate this possibility, I have proposed a series of experiments that will help to elucidate as well as characterize the role of gammasecretase S-nitrosylation on the overall production of amyloid-beta. Using multiple gamma-secretase activity assays, these experiments will test the ability of S-nitrosylation to stimulate gamma-secretase activity. In addition, the specific mechanism of gamma-secretase S-nitrosylation will be determined using both exogenous and endogenous sources of nitric oxide. If the results of these experiments show that gamma-secretase S-nitrosylation plays a significant role in the production of amyloid-beta, this would be a major discovery in the Alzheimer's field. Furthermore, it would have significant implications for possible new therapeutic methods for treating and perhaps even preventing the disease. Alzheimer's disease is a neurodegenerative illness that affects about 24 million people across the globe. This proposal presents a novel idea about what may be triggering Alzheimer's disease, suggesting that Alzheimer's may be caused by increased oxidative stress, which may be capable of modifying an important player in the disease. The results of this research could lead to new ways of treating Alzheimer's disease, including new, more specific forms of antioxidant therapy.