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

项目总结 已知与阿尔茨海默病和其他痴呆症相关的几种蛋白质经历液-液相 分离，这一过程可能对它们的功能至关重要。同时，这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纤维和沉积。分子 这些过程之间的联系尚不清楚，可能涉及中间的凝胶化步骤。照亮了 由于凝胶的粘滞性、动态性和异质性，其分子细节的性质一直很困难。 大自然。在这里，我们建议开发一种固态核磁共振(NMR)方法，它可以 描述这种蛋白质从液滴到凝胶和淀粉样蛋白状态的转变。 采样和实时。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 捕捉蛋白质必须经历的从本质无序状态到β的戏剧性转变- 片状富含淀粉样物质。这些信息将是理解正常和正常之间关系的关键 蛋白质功能和疾病，并开发有效的治疗方法、诊断工具和干预措施。我们将测试 并使用融合肉瘤(FUS)蛋白优化我们的治疗方法。FUS与额颞部有关 痴呆症(FTD)和肌萎缩侧索硬化症(ALS)，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 提供这些转化的分子描述。此外，我们建议利用我们的战略来 评估生物相关成分(如RNA)对这些过程的影响。我们的方法是 容易适应其他痴呆症相关蛋白，我们设想它将成为一种强大的分子 用于阐明健康和疾病中蛋白质行为的工具。

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.