Structure and Genesis of tau Aggregates

tau 聚集体的结构和成因

• 批准号: 10158623
• 负责人: Jeff Kuret
• 金额: $ 26.33万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-06-01 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10158623
• 关键词: Adopted; Affinity; Alzheimer' s Disease; Alzheimer' s disease diagnosis; Alzheimer' s disease pathology; Amyloid beta-Protein; Binding; Biological; Biological Models; Brain; Brain imaging; Cell Nucleus; Centrifugation; Clinical Trials; Complex; Conflict (Psychology); Data; Dementia; Descriptor; Development; Diagnosis; Diagnostic; Disease; Disease Vectors; Equilibrium; Event; Filament; Fostering; Generations; Goals; Human; Image; Kinetics; Lead; Length; Lesion; Ligand Binding; Ligands; Literature; Maps; Mass Spectrum Analysis; Mediator of activation protein; Methods; Microtubules; Modeling; Molecular; Molecular Conformation; Molecular Probes; Morphology; Nature; Nerve Degeneration; Nervous system structure; Neurofibrillary Tangles; Neurons; Pathogenesis; Pathology; Pathway interactions; Patients; Peptides; Pharmacology; Population; Positron-Emission Tomography; Process; Research; Role; Site; Source; Staging; Structure; Study Section; Surface; Surrogate Markers; Tauopathies; Testing; Therapeutic Agents; Thermodynamics; Toxic effect; Transgenic Organisms; Work; aggregation pathway; beta pleated sheet; biophysical techniques; chemical synthesis; cheminformatics; density; dimer; disease diagnosis; drug discovery; extracellular; inhibitor/antagonist; insight; mathematical model; molecular dynamics; monomer; novel; novel diagnostics; novel therapeutics; overexpression; polymerization; prion-like; radiotracer; single molecule; small molecule; tau Proteins; tau aggregation; tomography

Project Summary/Abstract The study of tau misfunction in tauopathic neurodegenerative disorders such as Alzheimer's disease is at a crossroads. Recent discoveries point to tau aggregation as being essential for prion-like spread of misfolding from neuron to neuron, implying a key role for aggregation in neurodegeneration, yet are contradicted by evidence from transgenic tau overexpression models that aggregation lies downstream of toxicity and may actually be neuroprotective. Indeed, it is well established that tau is hyperphosphorylated in disease, and that this event alone can lead to loss of microtubule function irrespective of aggregation, yet a clinical trial involving a potent inhibitor of tau hyperphosphorylation failed to modify the course of a human tauopathy. Classic studies showed that filamentous aggregates dominate the population of tau that accumulates in authentic neurofibrillary lesions, but other evidence implicates soluble oligomers potentially unrelated to cross-β-sheet structure as mediators of tau misfunction. With respect to aggregation kinetics, recent work has identified a role for secondary processes such as breakage and secondary nucleation that produce abundant small species, yet authentic lesions are dominated by aggregates that adopt filamentous morphology and achieve substantial lengths. Small-molecules that bind to tau aggregates or modulate their formation have been disclosed in the literature, but the mechanisms through which they act are ambiguous or involve substantial off-target liability. As a result of these conflicting ideas, the full potential of tau lesion pharmacology remains ambiguous. This project seeks to harmonize the many disparate observations made on tau aggregation and pharmacology using a biophysical approach. First, it will characterize and quantify tau aggregation kinetics while including a novel secondary pathway involving aggregate annealing. The analysis will be extended to the level of energetics, and to the relationship between aggregate structure and biological toxicity. Second, it will identify descriptors of ligand binding to tau aggregates, providing insight into the molecular features that influence binding affinity and therefore utility for premortem diagnosis. Finally, it will characterize the mechanism of action of non-covalent tau aggregation inhibitors associated with clearance of tau aggregates, including the nature of their binding targets, and the structure of their protective complexes. Successfully completed, the project will impact the field by clarifying targets for tauopathy drug discovery and by deducing molecular concepts important for optimizing premortem diagnostic agents.

项目概要/摘要 对 tau 蛋白病神经退行性疾病（如阿尔茨海默病）中 tau 蛋白功能失调的研究正在进行中 十字路口。最近的发现表明 tau 蛋白聚集对于错误折叠的类似朊病毒的传播至关重要 从神经元到神经元，暗示聚集在神经退行性变中的关键作用，但与 来自转基因 tau 过度表达模型的证据表明，聚集位于毒性的下游，并且可能 实际上具有神经保护作用。事实上，众所周知，tau 在疾病中过度磷酸化，并且 仅此事件就可能导致微管功能丧失，无论聚集如何，但一项临床试验涉及 tau 蛋白过度磷酸化的有效抑制剂未能改变人类 tau 蛋白病的进程。经典的 研究表明，丝状聚集体在真实的 tau 蛋白群体中占主导地位 神经原纤维病变，但其他证据表明可溶性寡聚体可能与跨β折叠无关 结构作为 tau 功能失调的调节者。关于聚集动力学，最近的工作已经确定了一个作用 对于产生大量小物质的二次过程，例如断裂和二次成核， 然而真正的病变主要是采用丝状形态的聚集体，并达到显着的效果 长度。结合 tau 聚集体或调节其形成的小分子已在 文献，但它们的作用机制不明确或涉及重大的脱靶责任。 由于这些相互矛盾的观点，tau 损伤药理学的全部潜力仍然不明确。 该项目旨在协调对 tau 聚集和 使用生物物理方法的药理学。首先，它将表征和量化 tau 聚集动力学 同时包括涉及聚集退火的新型二级途径。分析将扩展到 能量水平，以及聚集体结构和生物毒性之间的关系。其次，它会 识别配体与 tau 聚集体结合的描述符，提供对分子特征的深入了解 影响结合亲和力，从而影响尸前诊断的效用。最后，它将表征 与 tau 聚集体清除相关的非共价 tau 聚集抑制剂的作用机制， 包括其结合靶标的性质及其保护复合物的结构。成功地 完成后，该项目将通过阐明 tau 蛋白病药物发现的目标并推论来影响该领域 分子概念对于优化尸检诊断剂很重要。