What are the structural elements of amyloids that determine their toxicity?

淀粉样蛋白的哪些结构元素决定了其毒性？

• 批准号: 2742137
• 金额: --
• 依托单位: University of Southampton
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2742137
• 关键词: What; structural; elements; amyloids; determine

Neurodegenerative diseases are characterised by the formation of insoluble deposits within the brain which are rich in amyloid fibrils arising from the misfolding of proteins. Neurodegenerative diseases are characterised by the formation of insoluble deposits within the brain which are rich in amyloid fibrils arising from the misfolding of proteins. Recent studies have revealed that the toxicity of fibrils depends on their structural properties, with different polymorphs resulting in a range of 'strains' that display varying levels of toxicity. A major challenge in characterising fibril polymorphism is the hierarchical complexity, with polymorphism exhibited at the level of monomer folding, protofibril packing and fibril assembly. At each level, differences in protein folding and packing can influence interactions with binding partners, such as the receptors expressed in neurons or immune cells, influencing the toxicity and spread of amyloid deposits within the brain. This PhD project will investigate how the environment and the presence of ex-vivo amyloid fibrils (e.g. from experimental models, cerebrospinal cord fluid or human post-mortem tissue) influences the molecular-fold and packing of higher order structures formed from amyloid-beta peptide and alpha-synuclein - the proteins implicated in Alzheimer's and Parkinson's Disease respectively. To achieve this, we will use the complementary methods of solid-state NMR, which characterises the molecular fold, and atomic force microscopy which reports on the higher-order structures formed. The toxicity of each species formed will be assessed using in-vitro neuronal and/or glial cell culture models to provide a correlate of fibril structure with progression and severity of the disease observed in patients. The formation of a given polymorph is dependent on the exact conditions employed, and to date no such systematic study correlating the hierarchical structure of the fibril with toxicity has been reported. These studies will address how variations in molecular structure guide fibril assembly and identify at which level fibril polymorphism influences the toxicity the structure exhibit. Such data will facilitate the targeting of amyloid/cell interactions, aiding the management of neurodegenerative diseases.

神经退行性疾病的特征在于脑内形成不溶性沉积物，其富含由蛋白质错误折叠产生的淀粉样原纤维。神经退行性疾病的特征在于脑内形成不溶性沉积物，其富含由蛋白质错误折叠产生的淀粉样原纤维。最近的研究表明，原纤维的毒性取决于它们的结构特性，不同的多晶型物导致一系列显示不同毒性水平的“菌株”。表征原纤维多态性的一个主要挑战是层次复杂性，在单体折叠、原纤维包装和原纤维组装的水平上表现出多态性。在每个层面上，蛋白质折叠和包装的差异可以影响与结合伴侣的相互作用，例如神经元或免疫细胞中表达的受体，从而影响大脑内淀粉样蛋白沉积物的毒性和扩散。这个博士项目将研究环境和离体淀粉样纤维的存在（例如来自实验模型，脑脊液或人类死后组织）如何影响淀粉样β肽和α-突触核蛋白形成的高阶结构的分子折叠和包装-分别涉及阿尔茨海默氏症和帕金森氏症的蛋白质。为了实现这一点，我们将使用固态NMR的互补方法，其特征在于分子折叠，和原子力显微镜，其报告形成的高阶结构。将使用体外神经元和/或神经胶质细胞培养模型评估形成的每种物质的毒性，以提供原纤维结构与患者中观察到的疾病进展和严重程度的相关性。给定多晶型物的形成取决于所用的确切条件，并且迄今为止还没有报道将原纤维的分级结构与毒性相关联的这种系统性研究。这些研究将解决如何在分子结构的变化指导原纤维组装，并确定在何种程度上原纤维多态性影响毒性的结构表现。这些数据将促进淀粉样蛋白/细胞相互作用的靶向，有助于神经退行性疾病的管理。