Pathologic protein folding and human disease

病理性蛋白质折叠与人类疾病

• 批准号: 7080008
• 负责人: DAVID B. TEPLOW
• 金额: $ 154.72万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7080008
• 关键词: Alzheimer' s disease; amyloid proteins; amyloidosis; molecular pathology; neuropathology; protein folding

DESCRIPTION (provided by applicant): Diseases caused by pathologic protein folding are among the most devastating suffered by the aged. These diseases include Alzheimer's, Huntington's, Parkinson's, familial amyloid polyneuropathy, and prion. Each is a fatal disorder causing progressive cognitive and physical decline. Each is linked to aberrant folding of proteins that results in protein dysfunction. Dysfunction comes both from intrinsic changes in protein monomer structure and protein self-association (aggregation). The latter phenomenon occurs frequently in the dementing illnesses, of which Alzheimer's disease (AD) is the most common. In AD, the amyloid beta-protein (Abeta) self-associates to form oligomeric structures that circulate in plasma and cerebrospinal fluid. As the disease progresses, deposits of Aa are found in increasing number and size in the brain. These deposits, termed "amyloid plaques," contain fibrillar polymers of Abeta. Most cases of AD are not linked to mutations in the cognate structural gene for Abeta. This raises the questions of why pathologic folding and assembly of Abeta occur and why disease incidence increases so sharply after the age of 65. AD is not unique in these respects, as other dementing illnesses also are "diseases of aging." The general problem area addressed by this Program Project (Program) is pathologic protein folding and assembly, as exemplified by Abeta. We hypothesize that conformational changes in Abeta lead to oligomerization and that the resulting oligomeric assemblies are the proximate neurotoxins causing AD. To test this hypothesis, we propose two long-term specific aims: 1. To understand, at the most fundamental biophysical and cellular levels, how aberrant folding of proteins produces human disease. 2. To translate this knowledge into the design and implementation of new therapeutic agents. To accomplish these aims, five principal investigators at four different American universities have joined together to create a tightly-integrated program comprising two administrative cores and five projects. Our long-term strategy seeks first to establish a cohesive and productive research enterprise focused on AD and Abeta. We make this choice because AD is the most common cause of late-life dementia, its incidence is predicted to increase significantly, and Abeta assembly has proven to be archetypal for amyloid proteins. This last point is important, because the Program is designed to advance our understanding of AD and provide new technologies applicable in studies of folding and assembly of other amyloid and non-amyloid proteins. We thus envision the significance of the Program extending beyond solely AD.

描述（由申请人提供）：由病理蛋白质折叠引起的疾病是老年人遭受的最具破坏性的疾病。这些疾病包括阿尔茨海默氏症，亨廷顿，帕金森氏症，家族性淀粉样蛋白多神经病和prion。每种都是致命的疾病，导致进行性认知和身体下降。每个都与导致蛋白质功能障碍的蛋白质异常折叠有关。 功能障碍既来自蛋白质单体结构的内在变化，又来自蛋白质自我关联（聚集）。后一种现象经常发生在痴呆疾病中，其中阿尔茨海默氏病（AD）是最常见的。在AD中，淀粉样蛋白β-蛋白质（ABETA）自缔约方形成在血浆和脑脊液中循环的寡聚结构。随着疾病的发展，大脑中的数量和大小越来越大。这些沉积物称为“淀粉样蛋白斑块”，包含Abeta的原纤维聚合物。大多数AD病例与Abeta的同源结构基因中的突变无关。这就提出了一个问题，即为什么会发生病理性折叠和组装Abeta以及为什么在65岁之后疾病发病率如此急剧增加。在这些方面，AD并不是独一无二的，因为其他痴呆疾病也是“衰老疾病”。该计划项目（程序）解决的一般问题区域是病理蛋白质折叠和组装，如Abeta所示。我们假设ABETA的构象变化导致寡聚，而所得的低聚组件是导致AD的近端神经毒素。为了检验这一假设，我们提出了两个长期特定目标： 1。了解，在最基本的生物物理和细胞水平上，蛋白质的异常折叠如何产生人类疾病。 2。将这些知识转化为新的治疗剂的设计和实施。 为了实现这些目标，美国四所不同大学的五名主要调查员共同创建了一个紧密整合的计划，其中包括两个行政核心和五个项目。我们的长期战略首先寻求建立一个专注于AD和Abeta的凝聚力和生产性研究企业。我们之所以做出选择，是因为AD是晚期痴呆症的最常见原因，因此预计其发病率将大大增加，而Abeta组装已被证明是淀粉样蛋白的原型。最后一点很重要，因为该程序旨在提高我们对AD的理解，并提供适用于其他淀粉样蛋白和非淀粉样蛋白的折叠和组装研究的新技术。因此，我们设想了该计划的重要性，该计划仅超出了AD。