Structural studies of amyloid beta globulomers with EPR spectroscopy

利用 EPR 光谱法研究淀粉样蛋白球聚体的结构

• 批准号: 9240418
• 负责人: Zhefeng Guo
• 金额: $ 38.75万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-15 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9240418
• 关键词: Age; Alzheimer' s Disease; Amyloid; Amyloid Fibrils; Amyloid beta-Protein; Architecture; Data; Dementia; Disease; Docking; Drug Design; Electron Spin Resonance Spectroscopy; Electrons; Functional disorder; Goals; Healthcare; Healthcare Systems; Heterogeneity; Huntington Disease; Knowledge; Light; Longevity; Measurement; Measures; Modeling; Mutagenesis; Neurodegenerative Disorders; Neurotoxins; Non-Insulin-Dependent Diabetes Mellitus; Pain; Parkinson Disease; Pathogenesis; Pharmaceutical Preparations; Positioning Attribute; Prevalence; Protein Isoforms; Proteins; Public Health; Publishing; Research; Resolution; Risk Factors; Scanning; Site; Site-Directed Mutagenesis; Spin Labels; Structural Models; Structure; Synapses; System; Techniques; Time; Validation; abeta accumulation; abeta oligomer; abeta toxicity; alpha helix; base; beta pleated sheet; design; drug development; exhaustion; human disease; human very old age (85+); insight; intermolecular interaction; mutant; nanosecond; neuron loss; neurotoxicity; programs; protein structure prediction; success

Project Summary/Abstract Alzheimer’s disease, the major cause of dementia, is a fatal neurodegenerative disorder. The primary risk factor for Alzheimer’s disease is age. The prevalence of Alzheimer’s disease increases dramatically when people reach 65 years or older, reaching nearly 50% for people of >85 years old. Therefore, Alzheimer’s disease poses an enormous challenge to the healthcare system, and is a major obstacle for longevity. Extensive scientific research has identified soluble Aβ aggregates, collectively termed “oligomers”, as the primary neurotoxins that cause synapse dysfunction and neuronal death. Detailed structural knowledge on these Aβ oligomers would shed light on the basis of neurotoxicity and facilitate drug development to cure Alzheimer’s disease. Unfortunately, the progress on this front has been painfully slow. In this project, we propose to characterize the structure of Aβ globulomers formed by the 42-residue isoform of Aβ protein. Our preliminary studies have shown that, with electron paramagnetic resonance (EPR) spectroscopy, we were able to resolve structural heterogeneity and reveal the antiparallel architecture in Aβ oligomers. This project will build upon these preliminary studies and further tackle four specific aims. First, we will study the detailed secondary structure of Aβ42 globulomers using spin label mobility analysis at all 42 residue positions. Second, we will characterize the tertiary structure using intra-molecular distance measurements. Third, we will characterize the quaternary structure through inter-molecular distance analysis. Fourth, we will use protein structure prediction program Rosetta to model the structure of Aβ42 globulomers and cross-validate the top models using mutagenesis approaches. The field of Alzheimer’s research has suffered from a lack of accurate structural models of Aβ oligomers. Success in this project will fill this gap and provide unprecedented insights into the structures of Aβ42 oligomers. The structural knowledge on these oligomers will greatly facilitate the overall effort in understanding and treating Alzheimer’s disease and other amyloid-involved human diseases, including Parkinson’s, Huntington’s, and type 2 diabetes.

项目概要/摘要 阿尔茨海默病是痴呆症的主要原因，是一种致命的神经退行性疾病的主要风险。 阿尔茨海默病的一个因素是年龄，当年龄增加时，阿尔茨海默病的患病率会急剧增加。 人达到65岁以上，>85岁的人达到近50%，因此，阿尔茨海默病。 疾病给医疗保健系统带来了巨大挑战，也是长寿的主要障碍。 广泛的科学研究已确定可溶性 Aβ 聚集体，统称为“低聚物”，作为 导致突触功能障碍和神经元死亡的主要神经毒素的详细结构知识。 这些 Aβ 寡聚物将揭示神经毒性的基础，并促进药物开发以治愈疾病 不幸的是，在这个项目中，我们在这方面的进展非常缓慢。 提议表征由 Aβ 蛋白的 42 个残基亚型形成的 Aβ 球聚体的结构。 初步研究表明，利用电子顺磁共振（EPR）光谱，我们能够 该项目将解决结构异质性并揭示 Aβ 寡聚物的反平行结构。 在这些初步研究的基础上，我们将进一步研究四个具体目标。 使用自旋标签迁移率分析对所有 42 个残基位置进行 Aβ42 球聚体的二级结构。 我们将使用分子内距离测量来表征三级结构。 第四，我们将使用蛋白质来表征四级结构。 结构预测程序 Rosetta 用于模拟 Aβ42 球聚体的结构并交叉验证顶部 阿尔茨海默氏症研究领域一直缺乏准确的模型。 Aβ 寡聚物的结构模型。该项目的成功将填补这一空白并提供前所未有的见解。 这些寡聚物的结构知识将极大地促进 Aβ42 寡聚物的结构。 在理解和治疗阿尔茨海默病和其他与淀粉样蛋白相关的人类疾病方面的总体努力， 包括帕金森病、亨廷顿病和 2 型糖尿病。