Structure and Genesis of tau Aggregates

项目摘要/摘要 阿尔茨海默病等神经退行性疾病中tau功能障碍的研究正在进行中。 十字路口。最新的发现表明，tau聚集是Pron类错误折叠扩散的关键 从神经元到神经元，暗示了聚集在神经退化中的关键作用，但与 来自转基因tau过表达模型的证据表明，聚集位于毒性的下游，并可能 实际上是起到神经保护作用。事实上，众所周知，tau在疾病中过度磷酸化，而且 这一事件本身就可以导致微管功能的丧失，而不考虑聚集，但临床试验涉及 一种有效的tau过度磷酸化抑制剂未能改变人类紧张症的病程。经典 研究表明，在正品中积累的tau种群中主要是丝状聚集体。 神经原纤维损害，但其他证据表明，可溶低聚物可能与跨β-Sheet无关 结构作为tau故障的中介物。关于聚集动力学，最近的工作已经确定了一个角色 对于产生大量小物种的二次过程，如破碎和二次成核， 然而，真正的皮损主要是采用丝状形态的聚集体，并实现实质性 长度。与tau聚集体结合或调节其形成的小分子已在 但是，他们采取行动的机制含糊不清，或者涉及大量的脱离目标的责任。 由于这些相互矛盾的想法，tau损伤药理学的全部潜力仍然不明确。 这个项目寻求协调许多关于tau聚合和tau聚合的不同观察结果 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。 同时包括一种新的涉及聚集体退火的二次路径。这一分析将扩展到 能量学水平，以及团聚体结构与生物毒性的关系。其次，它将 识别配体与tau聚集体结合的描述符，提供对以下分子特征的洞察 影响结合亲和力，因此可用于死前诊断。最后，它将描述 与清除tau聚集体相关的非共价tau聚集抑制剂的作用机制， 包括它们的结合靶标的性质，以及它们的保护性络合物的结构。成功 该项目完成后，将通过澄清直肠疗法药物发现的目标和通过推断 分子概念对优化死前诊断试剂很重要。

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.