Structural and mechanistic studies of amyloids related to Alzheimer's disease and Parkinson's disease using engineered binding proteins

使用工程结合蛋白对与阿尔茨海默病和帕金森病相关的淀粉样蛋白进行结构和机制研究

• 批准号: 63689995
• 负责人: Professor Dr. Wolfgang Hoyer
• 金额: --
• 依托单位: Institut für Physikalische Biologie
• 依托单位国家: 德国
• 项目类别: Research Fellowships
• 财政年份: 2008
• 资助国家: 德国
• 起止时间: 2007-12-31 至 2008-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/63689995?language=en
• 关键词: Structural; mechanistic; studies; amyloids; related

The oligomerization and aggregation of the Alzheimer Aß peptide (Aß) resulting in amyloid plaque formation has been implicated as a key step in Alzheimer s disease (AD) pathogenesis. Consequently, anti-amyloid approaches, which target the production, aggregation and clearance of Aß, constitute the focus of current efforts to develop AD therapeutics. The goal of the present proposal is to support such approaches by providing insight into the molecular aspects of Aß oligomerization, fibril formation, and disaggregation. The suggested research project takes advantage of an engineered binding protein (affibody) which is capable of stabilizing monomeric Aß. First, the Aß-specific affibody will be employed to investigate the equilibria and transitions between the monomeric and the disease-related oligomeric and fibrillar states of Aß (i) in the test tube by NMR spectroscopy, and (ii) in a fly model of AD. Second, the NMR structures of the affibody complexes of the particularly toxic Aß(1- 42) and arctic variants of Aß will be compared with the previously determined complex structure of Aß(1-40) in order to identify potential differences in the conformational preferences of the peptides. Third, the interaction of the protein a-synuclein, which forms amyloid linked to Parkinson s disease, with an a-synucleinspecific affibody will be characterized biophysically and structurally. Potential similarities with the Aß-specific affibody would elucidate commonalities of amyloidogenic proteins and might suggest a general therapeutic approach towards amyloid diseases.

阿尔茨海默病S病(AD)发病机制中的一个关键步骤是导致阿尔茨海默病患者淀粉样斑块形成的阿尔茨海默氏肽的寡聚和聚集。因此，以产生、聚集和清除Aü为靶点的抗淀粉样蛋白方法，构成了目前开发AD治疗药物的重点。本提案的目标是通过提供对A？齐聚、纤维形成和解聚的分子方面的洞察来支持这种方法。建议的研究项目利用了一种能够稳定单体A？的工程化结合蛋白(亲和体)。首先，通过核磁共振波谱，我们将使用A？其次，为了识别多肽构象偏好的潜在差异，将特别有毒的A？(1-42)和北极变种A？的仿体复合体的核磁共振结构与先前确定的A？(1-40)的复杂结构进行比较。第三，形成与帕金森S病相关的淀粉样蛋白的a-突触核蛋白与a-突触核特异性亲和体的相互作用将从生物物理和结构上进行表征。与Aü特异性亲和抗体的潜在相似性将阐明淀粉样蛋白的共性，并可能建议一种治疗淀粉样蛋白疾病的一般方法。