Structural transformations of dementia-related proteins: droplets, gels and amyloids

痴呆相关蛋白质的结构转变：液滴、凝胶和淀粉样蛋白

• 批准号: 10055682
• 负责人: Galia Debelouchina
• 金额: $ 41.34万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-15 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10055682
• 关键词: Alzheimer' s Disease; Alzheimer' s disease related dementia; Amyloid; Amyloid Fibrils; Behavior; Binding; Biological; Brain; Cells; Complement; Cryoelectron Microscopy; Dementia; Deposition; Development; Diagnostic; Disease; Environment; Fluorescence; Frontotemporal Dementia; Gel; Goals; Health; Image; Imaging Device; In Vitro; Intervention; Investigation; Lead; Length; Liquid substance; Magic; Methodology; Molecular; NMR Spectroscopy; Nature; Nuclear Magnetic Resonance; Pathologic; Patients; Phase; Phase Transition; Preparation; Process; Property; Protein Dynamics; Protein Region; Proteins; Published Comment; RNA; RNA-Binding Proteins; Reporting; Resolution; Sampling; Structure; System; Techniques; Testing; Therapeutic Agents; Time; amyloid formation; amyloid structure; base; beta pleated sheet; design; effective therapy; experimental study; frontotemporal lobar dementia-amyotrophic lateral sclerosis; novel diagnostics; novel therapeutics; protein function; protein structure; recruit; sarcoma; small molecule; solid state; solid state nuclear magnetic resonance; stress granule; structural biology; tau Proteins; tool

Project summary Several proteins related to Alzheimer’s disease and other dementias are known to undergo liquid-liquid phase separation, a process that may be essential for their function. At the same time, such proteins are often known to form amyloid fibrils and deposits in the brains of patients suffering from those conditions. The molecular connection between these processes is unclear and may involve an intermediate gelation step. Illuminating the properties of gels in molecular detail has been difficult due to their viscous, dynamic and heterogeneous nature. Here, we propose to develop a solid-state nuclear magnetic resonance (NMR) approach that can characterize the transformations of such proteins from the droplet to the gel and amyloid states in the same sample and in real time. Our goal is to characterize the elusive interactions that build the gel networks and to capture the dramatic transformations that proteins must undergo from the intrinsically disordered state to the β- sheet rich amyloid form. This information will be essential in understanding the relationship between normal protein function and disease and to develop effective therapies, diagnostic tools and interventions. We will test and optimize our approach with the fused in sarcoma (FUS) protein. FUS is associated with frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) and has a well characterized phase separation behavior that includes the formation of liquid droplets, gels and amyloids. Using our approach, we aim to provide a molecular description of these transformations. Furthermore, we propose to use our strategy to evaluate the influence of biologically relevant components such as RNA on these processes. Our approach is easily adaptable to other dementia-related proteins and we envision that it will become a powerful molecular tool in illuminating protein behavior in health and disease.

项目摘要 已知与阿尔茨海默氏病和其他痴呆症有关的几种蛋白质会经历液态液相 分离，可能对其功能至关重要的过程。同时，这种蛋白质通常是已知的 在患有这些疾病的患者的大脑中形成淀粉样蛋白原纤维和沉积物。分子 这些过程之间的连接尚不清楚，并且可能涉及中间凝胶化步骤。照亮 由于凝胶的粘性，动态和异质性，凝胶的特性很困难 自然。在这里，我们建议开发一种固态核磁共振（NMR）方法，可以 表征这种蛋白质从液滴到凝胶和淀粉样蛋白的转化 样本和实时。我们的目标是表征建立凝胶网络的难以捉摸的相互作用 捕获蛋白质必须从本质上无序状态到β-的戏剧性转变 丰富的淀粉样板形式。这些信息对于理解正常之间的关系至关重要 蛋白质功能和疾病，并开发有效的疗法，诊断工具和干预措施。我们将测试 并优化我们在肉瘤（FUS）蛋白中的融合的方法。 FUS与额颞相关 痴呆（FTD）和肌萎缩性侧硬化症（ALS），具有良好的相位分离 行为，包括形成液滴，凝胶和淀粉样蛋白的行为。使用我们的方法，我们的目标是 提供这些转换的分子描述。此外，我们建议使用我们的策略 评估生物学相关组件（例如RNA）对这些过程的影响。我们的方法是 易于适应其他与痴呆相关的蛋白质，我们设想它将成为强大的分子 阐明健康和疾病中蛋白质行为的工具。