Analysis of the Involvement of the Microtubule Associated Protein Tau in the Regulation and Dysregulation of Neuronal Microtubule Dynamics by Quantitative „Live Cell Imaging“

微管(MT)在神经细胞中特别重要，它们支持轴突和树突的形成和稳定，并确保有效的细胞内运输。因此，MT骨架的异常和微管相关蛋白(MAP)tau等细胞骨架蛋白聚集体的形成是几种神经退行性疾病的典型神经病理特征也就不足为奇了。定量的“活细胞成像”为仔细观察活的神经细胞的这些过程提供了可能。利用“单分子跟踪”(SMT)实验，我们以前发现tau在轴突样突起中的单个MT结合位点上显示出非常短的停留时间(~40ms)，然后它“跳”到下一个--这一特征，我们称之为“接吻和跳跃”。然而，对于理解“接吻和跳跃”机制及其生理和病理相关性的重要方面仍然是开放的。在第一个项目部分，我们计划研究影响tau在神经细胞中“亲吻和跳跃”相互作用的因素及其潜在的生理和病理后果。在第二个项目部分，我们计划确定与疾病相关的关键tau修饰，它会导致基于MT的活动的病理变化。我们还将对具有调节tau和MT动力学与疾病相关变化的能力的潜在药物进行细胞生物学表征，作为开发特定机制治疗方案的先决条件。

Microtubules (MT) are of particular importance in nerve cells, where they support the formation and stabilization of axons and dendrites, and ensure effective intracellular transport. Thus, it is not surprising that abnormalities of the MT skeleton, and the formation of aggregates of cytoskeletal proteins such as the microtubule-associated protein (MAP) tau are typical neuropathological features, which occur in several neurodegenerative diseases. Quantitative "live cell Imaging" has opened the possibility to scrutinize these processes in living neuronal cells. Using "single molecule tracking" (SMT) experiments we showed previously that tau exhibits a remarkably short dwell time (~40 ms) on a single MT-binding site in axon-like processes before it "hops" to the next one – a feature, which we termed "kiss and hop". However, important aspects for understanding the "kiss and hop" mechanism and its physiological and pathological relevance are still open. In a first project part, we plan to investigate the factors influencing the "kiss and hop" interaction of tau in nerve cells and its potential physiological and pathological consequences. In a second project part, we plan to identify critical disease-associated tau modifications, which lead to pathological changes in MT-based activities. We will also perform a cell biological characterization of potential drugs with the capacity to modulate disease-associated changes of tau and MT dynamics as a prerequisite to develop specific mechanism-based therapeutic options.