The structural basis for amyloid formation by human apolipoproteins

人类载脂蛋白形成淀粉样蛋白的结构基础

• 批准号: nhmrc : 208913
• 负责人: A/Pr Geoffrey Howlett
• 金额: $ 14.07万
• 依托单位国家: 澳大利亚
• 项目类别: NHMRC Project Grants
• 财政年份: 2002
• 资助国家: 澳大利亚
• 起止时间: 2002-01-01 至 2004-12-31
• 项目状态: 已结题
• 来源: https://researchdata.edu.au/structural-basis-amyloid-human-apolipoproteins/83060
• 关键词: structural; basis; amyloid; formation; human

Amyloid formation is considered an abnormal state of protein aggregation that accompanies numerous medical conditions, notably Alzheimer disease, Parkinson's disease, the transmissible spongiform encephalopathies (e.g. scrapie, Creutzfeldt-Jakob disease) and metabolic diseases such as diabetes. These diseases involve a variety of normally non-fibrillar proteins with at least 20 human proteins identified as components of different types of amyloid. The current wide publicity given to bovine spongiform encephalopathy (BSE) disease and the potential impact on human health highlights the importance of developing strategies for treating these conditions. The prevalence of apolipoproteins in atherosclerotic amyloid deposits and senile plaques suggests a general propensity for human apolipoproteins to form pathogenic amyloid fibrils. Our recent observations that lipid-free human apolipoprotein C-II (apoC-II) forms ribbon-like fibrils in vitro provides an experimental system to explore this phenomenon. We propose to determine the structural requirements for the formation of amyloid fibrils human apoC-II and whether lipid-free human apolipoproteins form mixed-amyloid fibrils. Future strategies for treatment require better information on amyloid structure, the potential for mixed amyloid formation and the role of in vivo factors such as lipids and macromolecular crowding in regulating amyloid growth.

淀粉样蛋白形成被认为是蛋白质聚集的异常状态，其伴随许多医学病症，特别是阿尔茨海默病、帕金森病、传染性海绵状脑病（例如羊瘙痒病、克雅氏病）和代谢疾病如糖尿病。这些疾病涉及多种正常非纤维蛋白，其中至少20种人类蛋白被鉴定为不同类型淀粉样蛋白的组分。目前对牛海绵状脑病（BSE）疾病及其对人类健康的潜在影响的广泛宣传突出了制定治疗这些疾病的战略的重要性。载脂蛋白在动脉粥样硬化淀粉样沉积物和老年斑中的普遍存在表明人载脂蛋白形成致病性淀粉样纤维的一般倾向。我们最近的观察，无脂质的人载脂蛋白C-II（apoC-II）在体外形成带状纤维提供了一个实验系统，以探索这一现象。我们建议，以确定淀粉样纤维的形成人类载脂蛋白C-II的结构要求，以及是否无脂质的人类载脂蛋白形成混合淀粉样纤维。未来的治疗策略需要有关淀粉样蛋白结构、混合淀粉样蛋白形成的可能性以及脂质和大分子拥挤等体内因素在调节淀粉样蛋白生长中的作用的更好信息。