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 已知与阿尔茨海默病和其他痴呆症相关的几种蛋白质会经历液-液相 分离，这是一个可能对其功能至关重要的过程。与此同时，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纤维和沉积物。分子 这些过程之间的联系尚不清楚，可能涉及中间胶凝步骤。照亮 由于凝胶的粘性、动态性和不均匀性，很难从分子细节上研究其性质 自然在这里，我们建议开发一种固态核磁共振（NMR）方法， 表征这种蛋白质从液滴到凝胶和淀粉样蛋白状态的转化， 样品和真实的时间。我们的目标是表征构建凝胶网络的难以捉摸的相互作用， 捕捉蛋白质必须经历的从固有无序状态到β- 富含淀粉样蛋白片。这些信息对于理解正常的 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 并优化我们与肉瘤融合蛋白（FUS）的方法。FUS与额颞 痴呆（FTD）和肌萎缩侧索硬化（ALS），并具有良好的相分离特征 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 提供了这些转变的分子描述。此外，我们建议利用我们的战略， 评估生物相关成分如RNA对这些过程的影响。我们的做法是 很容易适应其他与痴呆症相关的蛋白质，我们设想它将成为一个强大的分子， 阐明蛋白质在健康和疾病中的行为。