Structure of amyloid fibrils in human neurodegenerative diseases and aging

人类神经退行性疾病和衰老中淀粉样原纤维的结构

• 批准号: 10721721
• 负责人: BERNARDINO Francesco GHETTI
• 金额: $ 392.43万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-30 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10721721
• 关键词: Address; Age; Age of Onset; Aging; Alzheimer' s Disease; Alzheimer' s disease related dementia; Amino Acid Sequence; Amyloid; Amyloid Fibrils; Amyloid Proteins; Amyloid beta-Protein; Amyloid deposition; Amyloidosis; Animal Model; Binding; Brain; Brain region; British; Classification; Clinical; Cryoelectron Microscopy; Dementia; Deposition; Development; Diffuse; Diffuse Lewy Body Disease; Disease; Down Syndrome; Early Onset Alzheimer Disease; Early Onset Familial Alzheimer' s Disease; Environment; Ependymal Cell; Face; Filament; Future; Genetic; Genotype; Goals; Gossypium; Grain; Human; In Vitro; Individual; Inherited; International; Knowledge; Lead; Ligands; Maps; Mass Spectrum Analysis; Modeling; Molecular; Morphology; Multiple System Atrophy; Mus; Mutation; Nerve Degeneration; Neurodegenerative Disorders; Parkinson Disease; Pathology; Peptides; Pick Disease of the Brain; Positron-Emission Tomography; Post-Translational Protein Processing; PrP; Prion Diseases; Property; Protein Isoforms; Proteins; Recombinant Proteins; Recombinants; Resolution; Sampling; Scanning Electron Microscopy; Source; Specificity; Stains; Structure; Structure of choroid plexus; System; Tauopathies; Testing; Three-Dimensional Image; Time; Transgenic Mice; Transmission Electron Microscopy; Western Blotting; Wool; Work; alpha synuclein; amyloid structure; apolipoprotein E-4; autosome; brain tissue; cell type; cohort; extracellular; human model; in vivo; in vivo imaging; mRNA Differential Displays; mouse model; multidisciplinary; nanometer resolution; neurodegenerative dementia; neuropathology; novel; presenilin-1; protein TDP-43; protein aggregation; protein purification; protein structure; response; structural biology; synthetic peptide; tau Proteins; tau aggregation

Project Summary/Abstract Recently, significant progress in understanding tauopathies and how tau aggregates lead to neurodegeneration has been made by the description of the atomic structures of tau filaments from human brain. We have established that the morphology of tau filaments comprising of all six tau isoforms (3R+4R tau) in diseases associated with extracellular amyloid deposition is identical, regardless of the amino acid sequence of the amyloid subunit. To gain further understanding on how different amyloids elicit a tau response comprising of 3R+4R tau with a common fold (AD fold), we characterized the structures of filaments of human extracellular amyloid-β (Aβ) in Alzheimer disease (AD) and Prion protein amyloid (APrP) in Prion diseases. In addition, we characterized the structures of α-synuclein filaments in Diffuse Lewy body disease, Parkinson disease and Multiple system atrophy, and TMEM106B filaments in several neurodegenerative diseases and aging. The studies proposed in this MPI application are a logical continuation of this groundbreaking work. These studies are in response to PAR-22-208 “Structural Biology of Alzheimer's Disease Related Dementias (ADRDs) Proteinopathies” (R01) The main goals of this application are to continue to characterize, from brain tissue, the structure of filaments at high atomic-level resolution for future use in PET ligand development and other related purposes, with special emphasis on mutations/genotypes and sporadic versus familial forms of disease, different ages of onset (e.g. early vs. late onset), and presence of co-pathologies. In addition, we propose to characterize fibrils derived from in vivo sources such as relevant animal models and biologically relevant in vitro systems, and to synthesize, identify, and characterize amyloid-specific ligands. In order to achieve our goals, our proposal has three specific aims. The first is to perform cryo-EM studies on a large cohort of EOAD individuals with different APOE genotypes and age at onset, and familial EOAD individuals with different clinical, genetic and neuropathologic features. In addition, we will determine for the first time the structure of filaments in individuals with Down syndrome, familial British and Danish dementia and the structure and identity of Biondi bodies. Second, we will generate a cryo-EM map and determine the corresponding atomic models of filaments extracted from the brain of murine models and generate high-resolution 3D images of the amyloid structures. Lastly, we will characterize by cryo-EM the structure of recombinant tau and synthetic peptides homologous to Aβ, ABri and ADan and compare our results with the peptides isolated from human and animal models. We will also synthesize, identify, and characterize amyloid-specific ligands.

项目摘要/摘要 最近，理解扭曲病以及tau聚集物如何导致神经变性方面的重大进展 通过描述人脑的tau细丝的原子结构的描述。我们有 确定tau丝的形态完成了所有六种tau同工型（3R+4R tau） 与细胞外淀粉样蛋白沉积相关的是相同的 淀粉样蛋白亚基。为了进一步了解不同的淀粉样蛋白如何引起tau响应。 3r+4r tau具有公共折叠（AD折叠），我们表征了人类细胞外细丝的结构 阿尔茨海默氏病（AD）和prion蛋白淀粉样蛋白（APRP）中的淀粉样蛋白-β（Aβ）。另外，我们 表征了弥漫性路易疾病，帕金森氏病和 多种神经退行性疾病和衰老中的多系统萎缩和TMEM106B细丝。 在此MPI应用中提出的研究是这项开创性工作的逻辑延续。这些 研究是对PAR-22-208的回应，“阿尔茨海默氏病有关的痴呆症（ADRDS）的结构生物学 蛋白质”（R01） 该应用的主要目标是继续从脑组织中表征出细丝的结构 高原子水平的分辨率，用于宠物配体开发和其他相关目的的未来使用，并具有特殊 强调突变/基因型，零星与家庭形式的疾病，不同年龄的发作年龄（例如 早期与晚期发作）和共同病理学的存在。此外，我们建议表征来自 体内来源，例如相关的动物模型和与生物学相关的体外系统，并合成，合成， 识别和表征淀粉样淀粉样蛋白特异性的配体。为了实现我们的目标，我们的建议有三个特定的 目标。首先是对具有不同APOE的大量EOAD个体进行冷冻EM研究 发作时的基因型和年龄，以及具有不同临床，遗传和神经病理学的家族性EOAD个体 特征。此外，我们将首次确定具有下降的个体的细丝结构 综合征，英国和丹麦痴呆症以及Biondi尸体的结构和身份。第二，我们会的 生成冷冻EM图并确定从大脑提取的丝的相应原子模型 鼠模型并生成淀粉样结构的高分辨率3D图像。最后，我们将描述 通过冷冻EM，重组Tau和合成肽的结构与Aβ，Abri和Adan同源 将我们的结果与从人类和动物模型中分离出来的Petides进行比较。我们还将合成，识别， 并表征淀粉样蛋白特异性配体。