Quantitative investigations into the molecular mechanisms of amyloid fibril fragmentation

淀粉样原纤维断裂的分子机制的定量研究

• 批准号: BB/J008001/1
• 负责人: Wei-Feng Xue
• 金额: $ 52.1万
• 依托单位: University of Kent
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2012
• 资助国家: 英国
• 起止时间: 2012 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FJ008001%2F1
• 关键词: Quantitative; investigations; into; molecular; mechanisms

Amyloid fibrils are forms of protein that have received much recent attention through their association with numerous devastating human brain diseases. Examples include Alzheimer, Creutzfeldt-Jakob (CJD), Huntington and Parkinson diseases. Furthermore, the unusual physical characteristics of amyloid fibrils mean that they have the potential to become strong and stable engineered nanomaterials. Breaking amyloid fibrils into smaller pieces is a key process that must be fully understood if we are to understand how amyloid fibrils normally function in nature, and how they are involved in diseases so we can develop effective therapies against the amyloid-associated diseases. Nevertheless, the causes and consequences of amyloid fibril fragmentation remain a largely unexplored area of research. The long-term goal of this project is to resolve the molecular and cellular mechanisms of fibril fragmentation.Amyloid fibrils are assembled from whole or parts of normal proteins and the devastating human diseases associated with amyloid are linked to the way the amyloid fibrils are assembled and deposited in the brain or in other parts of the human body. However, amyloid fibrils have also been recognised as a class of natural protein forms, so-called 'functional amyloids'. Functional amyloids can play a number of important roles in bacteria, yeast and even humans. A sub-class of amyloids can spread between organisms by forming small seeds through the fragmentation of larger fibrils. This sub-class is referred to as prions and they exist in humans where they cause diseases such as CJD. In baker's yeast, they confer special cellular properties on the cells that are passed on from generation to generation; a form of 'protein gene'. To fully understand how prions are formed and transmitted requires that we understand how the prion seeds (which we call propagons) are generated through amyloid fibril fragmentation. Detailed characterisation of amyloid fibrils of different origins has revealed incredibly strong structures that are commonly only tens of nanometres thick but many micrometers long. The fragmentation property of amyloid fibrils is, however, the dominating factor for their stability. Fibril fragmentation is also an important factor in amyloid-associated disease because it influences the size and shape of the disease-associated forms of the fibrils, which are typically large clumps of aggregates. How easy do disease-associated prions spread, how fast are amyloid aggregates assembled and deposited, and how toxic are these aggregates to cells are important disease properties that are influenced by amyloid fibril fragmentation.To address these points, our goal is to answer the following questions: how are amyloid fibrils fragmented, how fast can they fragment, and how is fragmentation linked to their properties in living cells. Using a combination of experimental, theoretical and computational approaches, the fragmentation properties of three different amyloids will be studied: one that forms a prion in yeast, one that is associated with human disease, and the third is an artificial model system. The insights gained from this project will also be critical for further exploring amyloid fibrils as potential nanomaterial in technological applications, and will provide new insights that will facilitate the future development of therapeutic strategies against amyloid associated disease.

淀粉样纤维是蛋白质的一种形式，由于它们与许多毁灭性的人类大脑疾病有关，最近受到了极大的关注。例如阿尔茨海默病、克雅氏病、亨廷顿病和帕金森病。此外，淀粉样蛋白纤维的不同寻常的物理特性意味着它们有可能成为强大和稳定的工程纳米材料。如果我们想要了解淀粉样纤维在自然界中的正常功能，以及它们如何参与疾病，那么将淀粉样纤维分解成更小的片段是一个必须充分了解的关键过程，这样我们才能开发有效的治疗淀粉样蛋白相关疾病的方法。然而，淀粉样蛋白纤维断裂的原因和后果在很大程度上仍然是一个未被探索的研究领域。该项目的长期目标是解决纤维断裂的分子和细胞机制。淀粉样纤维由正常蛋白质的全部或部分组装而成，与淀粉样蛋白相关的毁灭性人类疾病与淀粉样纤维在大脑或人体其他部位组装和沉积的方式有关。然而，淀粉样蛋白纤维也被认为是一类天然的蛋白质形式，即所谓的“功能性淀粉样蛋白”。功能性淀粉样蛋白可以在细菌、酵母甚至人类中扮演许多重要的角色。淀粉样蛋白的一个亚类可以通过较大纤维的碎裂形成较小的种子，从而在有机体之间传播。这个亚类被称为Prion，它们存在于人类中，在那里它们会导致CJD等疾病。在面包师酵母中，它们赋予代代相传的细胞特殊的细胞特性；一种“蛋白质基因”。要完全了解Pron是如何形成和传递的，我们需要了解Prion种子(我们称之为传播子)是如何通过淀粉样原纤维碎裂而产生的。对不同来源的淀粉样纤维的详细特征揭示了令人难以置信的坚固结构，这些结构通常只有几十纳米厚，但许多微米长。然而，淀粉样蛋白纤维的碎裂特性是其稳定性的主要因素。纤维碎裂也是淀粉样蛋白相关疾病的一个重要因素，因为它影响与疾病相关的纤维形式的大小和形状，这些纤维通常是大团聚体。疾病相关的Prion传播有多容易，淀粉样聚集体组装和沉积的速度有多快，以及这些聚集体对细胞的毒性有多大，这些都是受淀粉样纤维碎裂影响的重要疾病属性。为了解决这些问题，我们的目标是回答以下问题：淀粉样纤维是如何碎裂的，它们可以多快地碎裂，以及在活细胞中，碎裂与它们的特性是如何联系在一起的。采用实验、理论和计算相结合的方法，将研究三种不同淀粉样蛋白的碎裂特性：一种是在酵母中形成普里恩，一种与人类疾病有关，第三种是人工模型系统。从这个项目中获得的见解对于进一步探索淀粉样纤维作为潜在的纳米材料在技术应用中也是至关重要的，并将提供新的见解，将促进未来开发针对淀粉样蛋白相关疾病的治疗策略。

项目成果

Amyloid particles facilitate surface-catalyzed cross-seeding by acting as promiscuous nanoparticles.

• DOI: 10.1073/pnas.2104148118
• 发表时间: 2021-09-07
• 期刊: Proceedings of the National Academy of Sciences of the United States of America
• 影响因子: 11.1
• 作者: Koloteva-Levine N;Aubrey LD;Marchante R;Purton TJ;Hiscock JR;Tuite MF;Xue WF
• 通讯作者: Xue WF

Insights into the dynamic trajectories of protein filament division revealed by numerical investigation into the mathematical model of pure fragmentation.

• DOI: 10.1371/journal.pcbi.1008964
• 发表时间: 2021-09
• 期刊: PLoS computational biology
• 影响因子: 4.3
• 作者: Tournus M;Escobedo M;Xue WF;Doumic M
• 通讯作者: Doumic M

Analysis of Toxic Amyloid Fibril Interactions at Natively Derived Membranes by Ellipsometry.

• DOI: 10.1371/journal.pone.0132309
• 发表时间: 2015
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Smith RA;Nabok A;Blakeman BJ;Xue WF;Abell B;Smith DP
• 通讯作者: Smith DP

Amyloid particles facilitate surface-catalyzed cross-seeding by acting as promiscuous nanoparticles

淀粉样蛋白颗粒通过充当混杂的纳米颗粒来促进表面催化的交叉播种

• DOI: 10.1101/2020.09.01.278481
• 发表时间: 2020
• 作者: Koloteva-Levine N

Dynamic prions revealed by magic.

通过魔法揭示动态朊病毒。

• DOI: 10.1016/j.chembiol.2014.02.001
• 发表时间: 2014
• 期刊: Chemistry & biology
• 作者: Tuite MF