Pathologic protein folding and human disease

由病理性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之一。这些疾病包括阿尔茨海默氏症、亨廷顿氏症、帕金森氏症、家族性淀粉样多发性神经病和朊病毒。每一种都是一种致命的疾病，会导致认知和身体的逐渐衰退。每一种都与导致蛋白质功能障碍的蛋白质异常折叠有关。 功能障碍来自蛋白质单体结构的内在变化和蛋白质自缔合（聚集）。后一种现象经常发生在痴呆性疾病中，其中阿尔茨海默病（AD）是最常见的。在AD中，淀粉样β蛋白（Abeta）自缔合形成在血浆和脑脊液中循环的寡聚体结构。随着疾病的进展，Aa的沉积物在大脑中的数量和大小都在增加。这些沉积物称为“淀粉样斑块”，含有Abeta的纤维状聚合物。大多数AD病例与Abeta同源结构基因的突变无关。这就提出了为什么Abeta会发生病理性折叠和组装，以及为什么65岁以后发病率会如此急剧增加的问题。AD在这些方面并不独特，因为其他痴呆症也是“衰老疾病”。“这个计划项目（计划）解决的一般问题领域是病理性蛋白质折叠和组装，如Abeta所示。我们推测，构象变化的Abeta导致寡聚化，并由此产生的寡聚体组件是最接近的神经毒素导致AD。为了验证这一假设，我们提出了两个长期的具体目标： 1.在最基本的生物物理和细胞水平上，了解蛋白质的异常折叠如何导致人类疾病。 2.将这些知识转化为新治疗药物的设计和实施。 为了实现这些目标，美国四所不同大学的五名主要研究人员联合起来创建了一个紧密集成的计划，包括两个管理核心和五个项目。我们的长期战略首先是建立一个专注于AD和Abeta的有凝聚力和生产力的研究企业。我们做出这个选择是因为AD是老年痴呆症最常见的原因，其发病率预计会显着增加，并且Abeta组装已被证明是淀粉样蛋白的原型。最后一点很重要，因为该计划旨在促进我们对AD的理解，并提供适用于其他淀粉样蛋白和非淀粉样蛋白折叠和组装研究的新技术。因此，我们设想该计划的意义不仅仅是AD。

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.