Amyloid Fibrils, Spherulites and Beyond: Unravelling Mechanisms that Control Protein Aggregation

当球状蛋白质从它们的天然构象变成部分未折叠或完全错误折叠时，它们经常聚集成许多分子的组装体。这种聚集发生的关键形式之一是所谓的淀粉样原纤维，分子非常规则地包装成含有大量β折叠的长原纤维。这些纤维与许多老年疾病和神经退行性疾病有关，如阿尔茨海默病和帕金森病。然而，在良性情况下也发现了相同的结构，例如当牛奶蛋白被热处理以导致酸奶和奶酪等食物的质地时。淀粉样蛋白原纤维不是唯一的聚集体形式，最近的研究已经确定了被称为球晶的超原纤维聚集体。这些也在患病的脑组织中发现，并且也已知在乳蛋白中形成。该项目旨在试图揭示控制这些不同聚集体何时以及如何形成的因素，以及是什么决定了它们之间的平衡。通过研究胰岛素和Abeta（与阿尔茨海默病相关的蛋白质）等模型蛋白质，我们的目标是探索蛋白质的电荷状态和表面存在的作用。相关的表面包括纳米颗粒的引入以及更宏观的表面。了解纳米颗粒对蛋白质聚集的影响是医疗保健的另一个主要推动力，该项目可能有助于解决这个问题。如果纳米颗粒被证明可以促进蛋白质聚集，这些研究将对纳米材料的细胞毒性和毒理学产生深远的影响。

When globular proteins become partially unfolded or completely misfolded from their native conformation they frequently aggregate into assemblies of many molecules. One of the key forms in which this aggregation occurs is the so-called amyloid fibril, a very regular packing of the molecules into long fibrils containing a significant amount of beta sheet. These fibrils are implicated in many of the diseases of old age and neurodegeneration, such as Alzheimer's and Parkinson's disease. However, this same structure is also found in benign situations, such as when milk proteins are heat-treated to lead to texture in foods such as yogurt and cheese. The amyloid fibril is not the only form of aggregate that can occur, and recent studies have identified suprafibrillar aggregates known as spherulites. These have also been found in diseased brain tissue, and are also known to form in the milk proteins. This project aims to try to uncover the factors that control when and how these different aggregates form, and what determines the balance between them. By working on model proteins such as insulin and Abeta (the protein associated with Alzheimer's disease) we aim to explore the role of the charge state of the protein and the presence of surfaces. The relevant surfaces include the introduction of nanoparticles as well as more macroscopic surfaces. Understanding the impact of nanoparticles for protein aggregation is another major thrust in healthcare which this project may help to address. If nanoparticles are shown to promote protein aggregation these studies will have far reaching implications for the cytotoxicity and toxicology of nanomaterials.