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.

项目概要 已知与阿尔茨海默病和其他痴呆症相关的几种蛋白质会经历液-液相 分离，这一过程可能对其功能至关重要，同时，此类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原纤维和沉积物。 这些过程之间的联系尚不清楚，并且可能涉及中间凝胶化步骤。 由于其粘性、动态性和异质性，凝胶的分子细节特性一直很困难 在这里，我们建议开发一种固态核磁共振（NMR）方法，可以 表征此类蛋白质从液滴到凝胶和淀粉样蛋白状态的转变 我们的目标是描述构建凝胶网络的难以捉摸的相互作用并进行实时分析。 捕捉蛋白质必须经历的从本质无序状态到 β- 状态的戏剧性转变 该信息对于理解正常淀粉样蛋白之间的关系至关重要。 我们将测试蛋白质功能和疾病，并开发有效的疗法、诊断工具和干预措施。 并利用与额颞叶相关的肉瘤融合蛋白 (FUS) 优化我们的方法。 痴呆 (FTD) 和肌萎缩侧索硬化症 (ALS) 并具有明确的相分离特征 我们的目标是利用我们的方法来实现包括液滴、凝胶和淀粉样蛋白的形成在内的行为。 此外，我们建议使用我们的策略来提供这些转变的分子描述。 评估RNA等生物学相关成分对这些过程的影响。 很容易适应其他痴呆相关蛋白，我们预计它将成为一种强大的分子 阐明健康和疾病中蛋白质行为的工具。