The influence of oxidative stress on protein structure and assembly in Alzheimer's and other neurodegenerative diseases

氧化应激对阿尔茨海默病和其他神经退行性疾病中蛋白质结构和组装的影响

• 批准号: 2457510
• 金额: --
• 依托单位: University of Sussex
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2020
• 资助国家: 英国
• 起止时间: 2020 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2457510
• 关键词: influence; oxidative; stress; protein; structure

Neurodegenerative diseases are primarily diseases of aging. During the aging process, we accumulate protein damage due to environmental influences and biological processes associated with oxidative stress. This project aims to investigate the overarching influence of oxidative stress on protein conformation and protein misfolding in vitro and in cells.The project will address the hypothesis that oxidative stress is a trigger for neurodegeneration during aging. To explore this question, the student will investigate the effect of oxidative environments on misfolding proteins in vitro and on neurons.Proteins associated with Alzheimer's Disease (AD) include Amyloid-beta, tau and Apolipoprotein E. Recent work in the Serpell laboratory in collaboration with Xue laboratory has highlighted the important role for oxidative stress in modulating protein structure and self-assembly. Apolipoprotein E4 is a risk factor for AD and we have recently shown that ApoE4 can self-assemble in vitro and this can be further influenced by oxidative conditions. Furthermore, ApoE4 neurons (taken from our human ApoE targeting replacement mouse colony) show enhanced vulnerability to oxidative environments than those expressing ApoE3. Neurons exposed to oxidative stress express increased amounts of ApoE protein in response.Abeta and tau are both self-assembling proteins that form amyloid fibrils in vitro. Both are influenced by oxidative environments resulting in the formation of a key marker for oxidative stress, called dityrosine crosslinks that form intermolecular covalent linkages. How these oxidative environments impact on self-assembly and toxicity of Abeta and tau in vitro and neurons remains unclear and will be a key important aspect of this project.The project will bring together the findings in cellular and in vitro environments to unify our understanding of how oxidative stress leads to markers of aging and results in increased risk of developing protein misfolding and neurodegenerative diseases.

神经退行性疾病主要是衰老疾病。在衰老过程中，由于环境影响和与氧化应激相关的生物过程，我们积累了蛋白质损伤。本项目旨在研究体外和细胞中氧化应激对蛋白质构象和蛋白质错误折叠的总体影响。该项目将解决氧化应激是衰老过程中神经退行性变的触发因素的假设。为了探索这个问题，学生将研究氧化环境对体外错误折叠蛋白质和神经元的影响。与阿尔茨海默病（AD）相关的蛋白质包括淀粉样蛋白β，tau蛋白和载脂蛋白E。Serpell实验室与Xue实验室合作的最新工作强调了氧化应激在调节蛋白质结构和自组装中的重要作用。载脂蛋白E4是AD的一个危险因素，我们最近发现ApoE4可以在体外自组装，这可以进一步受到氧化条件的影响。此外，ApoE4神经元（取自我们的人ApoE靶向替代小鼠群体）显示出比表达ApoE3的神经元对氧化环境的脆弱性增强。暴露于氧化应激的神经元表达大量的ApoE蛋白作为反应。Abeta和tau都是自组装蛋白，在体外形成淀粉样纤维。两者都受到氧化环境的影响，导致形成氧化应激的关键标志物，称为双酪氨酸交联，形成分子间共价键。这些氧化环境如何影响Abeta和tau在体外和神经元中的自组装和毒性尚不清楚，这将是该项目的一个关键重要方面。该项目将汇集细胞和体外环境中的发现，以统一我们对氧化应激如何导致衰老标志物并导致蛋白质错误折叠和神经退行性疾病风险增加的理解。