Pathologic protein folding and human disease

描述(申请人提供)：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普里昂。每一种都是一种致命的疾病，会导致认知和身体的进行性下降。每一种都与蛋白质的异常折叠有关，从而导致蛋白质功能障碍。功能障碍既源于蛋白质单体结构的内在变化，也源于蛋白质的自结合(聚集)。后一种现象多见于痴呆性疾病，其中阿尔茨海默病(AD)最为常见。在阿尔茨海默病中，淀粉样β蛋白(Abeta)自结合形成低聚结构，在血浆和脑脊液中循环。随着疾病的发展，AA在大脑中的沉积数量和大小都在增加。这些沉积物被称为“淀粉样斑块”，含有Abeta的纤维聚合物。大多数AD病例与Abeta的同源结构基因突变无关。这就提出了这样的问题：为什么会发生Abeta的病理性折叠和组装，为什么65岁以后发病率会急剧上升。在这些方面，AD并不是独一无二的，因为其他痴呆症也是“老年病”。本计划项目(Program)解决的一般问题领域是病理性蛋白质折叠和组装，如Abeta。我们假设Abeta的构象变化导致寡聚化，由此产生的寡聚体组装是导致AD的最接近的神经毒素。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剂的设计和实施。 为了实现这些目标，来自四所不同美国大学的五名首席研究人员联合起来，创建了一个紧密结合的项目，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的具有凝聚力和生产力的研究企业。我们之所以做出这一选择，是因为AD是老年痴呆最常见的原因，其发病率预计将显著增加，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的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限于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.