Structure and Genesis of tau Aggregates

项目总结/摘要 在tau蛋白病性神经退行性疾病如阿尔茨海默病中tau蛋白功能障碍的研究正处于一个新的阶段。 十字路口最近的发现指出，tau蛋白聚集是朊病毒样错误折叠传播的关键 从神经元到神经元，这意味着聚集在神经变性中的关键作用，但与 来自转基因tau蛋白过表达模型的证据表明，聚集位于毒性的下游， 实际上是神经保护的。事实上，已经确定tau蛋白在疾病中过度磷酸化， 这一事件本身可导致微管功能丧失，而与聚集无关，但一项涉及 tau蛋白过度磷酸化的有效抑制剂不能改变人tau蛋白病的进程。经典 研究表明，丝状聚集体占主导地位的tau群体， 但其他证据表明可溶性寡聚体可能与交叉β折叠无关 结构作为tau功能失调的介质。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如断裂和二次成核， 然而，真实的病变主要是聚集体，其采用丝状形态并实现实质性的 长度结合tau聚集体或调节其形成的小分子已经公开于 这些法律文献中有一些是明确的，但它们的作用机制不明确，或涉及大量的脱靶赔偿责任。 由于这些相互冲突的想法，tau病变药理学的全部潜力仍然模糊不清。 该项目旨在协调对tau聚集的许多不同观察， 药理学使用生物物理方法。首先，它将表征和量化tau聚集动力学 同时包括涉及聚集体退火的新的次级途径。分析将扩展到 能量学水平，以及聚集体结构与生物毒性之间的关系。二是会 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， 从而影响结合亲和力并因此影响其用于死前诊断的效用。最后，它将描述 与tau聚集体清除相关的非共价tau聚集抑制剂的作用机制， 包括其结合靶的性质和其保护性复合物的结构。成功 完成后，该项目将通过澄清tau蛋白病药物发现的目标和推导出 分子概念的重要优化死前诊断剂。

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.