Generation of Tau Prion Strains in Dividing Mammalian Cells

哺乳动物细胞分裂中 Tau 朊病毒株的产生

• 批准号: 8760218
• 负责人: David Winland Sanders
• 金额: $ 2.56万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-20 至 2015-09-19
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8760218
• 关键词: Address; Agar Gel Electrophoresis; Alzheimer' s Disease; Amyloid; Antibodies; Argyrophilic Grain Disease; Attention; Behavior; Biological Assay; Brain; Cells; Characteristics; Clinic; Collaborations; Data; Deposition; Detergents; Diagnosis; Disease; Etiology; Extracellular Protein; Frontotemporal Dementia; Generations; Health; Human; Hydrochloride Salt; Individual; Lead; Letters; Luciferases; Mammalian Cell; Measures; Metric; Microtubule-Associated Proteins; Molecular Conformation; Morphology; Mutation; Nervous system structure; Neurodegenerative Disorders; Patients; Peptide Hydrolases; Pick Disease of the Brain; Predisposition; Prions; Progressive Supranuclear Palsy; Proteins; Recombinants; Relative (related person); Research; Role; Sample Size; Sedimentation process; Seeds; Source; Tauopathies; Testing; Therapeutic; Toxic effect; Work; Yeasts; base; corticobasal degeneration; daughter cell; design; guanidinium; insight; polyglutamine; prevent; prion hypothesis; prion-like; synucleinopathy; tau Proteins; tau aggregation; tau-1

DESCRIPTION (provided by applicant): Tauopathies, a heterogeneous group of neurodegenerative diseases, feature insoluble deposits of the microtubule-associated protein tau. A causal role for tau misfolding in disease is supported by the fact that multiple mutations associated with an increased propensity for aggregation cause autosomally dominant forms of the disease. Previous work from our lab as well as from others' suggests that the tau protein can propagate misfolding from the outside to the inside of the cell, and between cells in a prion-like fashion. This mechanistic paradigm is also implicated in other disorders including synucleinopathies, polyglutamine expansion diseases, and frontotemporal dementia/ALS spectrum diseases. However, whether or not the proteins associated with these diverse diseases are true prions, defined by the ability to propagate unique conformations, is an unsettled matter. Preliminary data suggests that exogenous tau fibrils induce the misfolding of endogenously expressed tau repeat domain (RD, aa 244-372), which stably propagates its amyloid state to daughter cells as biochemically distinct prion strains. These conformations can be isolated from cells and re-introduced into na¿ve cells to seed self-propagating aggregates with the same phenotypic characteristics. Brain homogenates from human patients with different tauopathies induce the formation of unique tau aggregate strains. Building on preliminary data, the present work addresses two hypotheses: 1) Distinct strains are associated with distinct tauopathies; 2) There is a direct correlation between a strain's conformational stability and its ability to seed further aggregation and induce toxicity. If successful, this work will provide compelling evidence for tauopathies having a prion etiology and will gather mechanistic insight into the factors that dictate strain formation, strength, and toxicity. This research is significan because it could help lead to more accurate diagnosis of tauopathies, and to more precise antibody-based treatments that target extracellular protein, which are gaining increasing attention as potential therapies

描述（由申请人提供）：Tau病是一组异质性神经退行性疾病，其特征在于微管相关蛋白tau的不溶性沉积。tau错误折叠在疾病中的因果作用得到以下事实的支持：与聚集倾向增加相关的多个突变导致常染色体显性形式的疾病。我们实验室和其他人以前的工作表明，tau蛋白可以从细胞外部传播错误折叠到细胞内部，并以朊病毒样方式在细胞之间传播。这种机制范式也涉及其他疾病，包括突触核蛋白病、多聚谷氨酰胺扩增疾病和额颞叶痴呆/ALS谱系疾病。然而，与这些不同疾病相关的蛋白质是否是真正的朊病毒，由传播独特构象的能力来定义，是一个悬而未决的问题。初步数据表明，外源性tau纤维诱导内源性表达的tau重复结构域（RD，aa 244-372）的错误折叠，其稳定地将其淀粉样蛋白状态传播到子细胞作为生物化学上不同的朊病毒株。这些构象可以从细胞中分离出来，并重新引入到幼稚细胞中，以接种具有相同表型特征的自繁殖聚集体。来自患有不同tau蛋白病的人类患者的脑匀浆诱导独特tau聚集体菌株的形成。在初步数据的基础上，本工作解决了两个假设：1）不同的菌株与不同的tau蛋白病相关; 2）菌株的构象稳定性与其接种进一步聚集和诱导毒性的能力之间存在直接相关性。如果成功的话，这项工作将为具有朊病毒病因学的tau蛋白病提供令人信服的证据，并将收集对决定菌株形成，强度和毒性的因素的机制见解。这项研究具有重要意义，因为它可以帮助更准确地诊断tau蛋白病，以及更精确的靶向细胞外蛋白的基于抗体的治疗，这些治疗作为潜在的治疗方法越来越受到关注。