Structure and Genesis of tau Aggregates

tau 聚集体的结构和成因

基本信息

批准号：
9311789
负责人：
Jeff Kuret
金额：
$ 236.34万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
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/9311789
关键词：
Adopted Affinity Alzheimer&apos s Disease Amyloid beta-Protein Binding Biological Biological Models Brain Brain imaging Cell Nucleus Centrifugation Clinical Trials Complex Conflict (Psychology)Data Dementia Depressed mood Descriptor Development Diagnosis Diagnostic Dimerization 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

项目摘要

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.

项目摘要/摘要 tau神经退行性疾病（例如阿尔茨海默氏病）的tau功能障碍的研究正处于十字路口。最近的发现表明tau聚集对于像王子一样的折叠式传播至关重要从神经元到神经元，暗示着在神经变性中汇总的关键作用，但与来自转基因TAU过表达模型的证据，聚集在毒性的下游，可能确实，很明确，tau在疾病中被过度磷酸化，并且仅此事件就可以导致微管功能的丧失，而不论汇总如何 tau高磷酸化的潜在抑制剂未能改变人tauopathy的过程。经典的研究表明，丝状骨料主导着积累在真实的Tau的种群神经原纤维病变，但其他证据表明，固体低聚物可能与跨β-折叠无关结构是tau官方官方的介体。关于聚集动力学，最近的工作已经确定了一个角色对于产生丰富小物种的次要过程，例如破裂和二级成核，然而，真实的病变由采用丝状形态并实现实质性的聚集体主导长度。与tau聚集体结合或调节其形成的小分子已在文献，但是它们所采用的机制模棱两可或涉及实质性的脱离目标责任。由于这些矛盾的想法，Tau病变药理学的全部潜力仍然模棱两可。该项目旨在协调tau聚合和使用生物物理方法的药理学。首先，它将表征和量化tau聚合动力学同时包括一种新颖的次要途径涉及总退火。分析将扩展到能量水平，以及骨料结构与生物毒性之间的关系。其次，它将识别配体与tau聚集体的结合的描述子，提供对分子特征的见解影响结合亲和力，因此对预先诊断的实用性。最后，它将表征非共价tau聚集抑制剂的作用机理与清除tau聚集体相关的作用机理，包括其结合靶标的性质及其受保护复合物的结构。成功地完成后，该项目将通过透明tauopathy药物发现的目标和推论来影响该领域分子概念对于优化预先分类诊断剂很重要。