The Structural Biology of Amyloid Aggregation

淀粉样蛋白聚集的结构生物学

基本信息

批准号：
MR/T011149/1
负责人：
Neil Ranson
金额：
$ 97.61万
依托单位：
University of Leeds
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2020
资助国家：
英国
起止时间：
2020 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=MR%2FT011149%2F1
关键词：
Structural Biology Amyloid Aggregation

项目摘要

Diseases linked with the aggregation of proteins are a major threat to today's society, especially amongst our ageing population, and the public are today acutely aware of the threats posed by these diseases, which include Alzheimer's and Parkinson's diseases and other degenerative disorders. Proteins are the workhorses of all living organisms. They perform most of the functions required for life, and their dysfunction if left unchecked by the natural defence mechanisms of cells, can be hugely damaging to cellular function and healthy life. From the moment proteins are synthesised, they exist on a knife-edge, wherein changes to their sequence can lead to aggregation and disease. One of the commonest forms of protein misfolding diseases is amyloidosis, and more than 50 different proteins are currently known to cause amyloid diseases that include both rare disorders, such as dialysis-related amyloidosis (DRA), and major societal threats such as Parkinson's disease (PD). Unfortunately we are not able prevent, treat or cure most amyloid diseases and failures of clinical trials mean that we urgently need new inspiration to fire innovative ways of tackling amyloid disease. In this three year project, we will provide new insights into the structures of amyloid fibrils and the mechanism by which they form, hopefully providing a new impetus for therapeutic ideas. The time has never been better to make this step change. By exploiting recent advances in cryo-electron microscopy (cryo-EM), we will answer three fundamentally important and medically relevant questions: (i) how diverse is the amyloid fold, and (ii) how relevant are in vitro models of amyloid aggregation to the structures formed in patients, and (iii) how can we link amyloid sequence and structure to human disease? Working closely with physicians who are expert in systemic and neurodegenerative disorders, and focussing on alpha-synuclein (involved in Parkinson's disease) and beta2-microglobulin (associated with dialysis-related and systemic amyloidoses), we will achieve these aims by determining the 3D structures of amyloid fibrils grown in vitro and comparing them with fibrils extracted from human tissue. Overall, therefore, the work will yield new insights into amyloid structure, stability and function and new understandings of how these fascinating assemblies contribute to the cellular dysfunction that may led to disease.

与蛋白质聚集相关的疾病是当今社会的主要威胁，特别是在我们的老龄化人口中，当今公众敏锐地意识到这些疾病所带来的威胁，其中包括阿尔茨海默病、帕金森病和其他退行性疾病。蛋白质是所有生物体的主力。它们执行生命所需的大部分功能，如果不受细胞自然防御机制的控制，它们的功能障碍可能会对细胞功能和健康生活造成巨大损害。从蛋白质合成的那一刻起，它们就存在于刀刃上，其中序列的改变可能导致聚集和疾病。最常见的蛋白质错误折叠疾病之一是淀粉样变性，目前已知有超过 50 种不同的蛋白质会导致淀粉样变性疾病，其中包括罕见疾病，例如透析相关淀粉样变性 (DRA)，以及主要的社会威胁，例如帕金森病。 PD）。不幸的是，我们无法预防、治疗或治愈大多数淀粉样蛋白疾病，临床试验的失败意味着我们迫切需要新的灵感来激发解决淀粉样蛋白疾病的创新方法。在这个为期三年的项目中，我们将对淀粉样原纤维的结构及其形成机制提供新的见解，希望为治疗思路提供新的推动力。现在正是做出这一步改变的最佳时机。通过利用冷冻电子显微镜 (cryo-EM) 的最新进展，我们将回答三个基本重要且与医学相关的问题：(i) 淀粉样蛋白折叠的多样性如何，以及 (ii) 淀粉样蛋白聚集的体外模型与患者体内形成的结构，以及 (iii) 我们如何将淀粉样蛋白序列和结构与人类疾病联系起来？与系统性和神经退行性疾病方面的专家密切合作，重点关注 α-突触核蛋白（与帕金森病有关）和 β2-微球蛋白（与透析相关和系统性淀粉样变性相关），我们将通过确定 3D 结构来实现这些目标体外生长的淀粉样原纤维，并将其与从人体组织中提取的原纤维进行比较。因此，总的来说，这项工作将对淀粉样蛋白的结构、稳定性和功能产生新的见解，并对这些令人着迷的组装如何导致可能导致疾病的细胞功能障碍产生新的理解。