Real-Time Tracking of Vesicles in Living Cells Reveals That Tau-Hyperphosphorylation Suppresses Unidirectional Transport by Motor Proteins

Eunsang Lee, Donghee Kim, Yo Han Song, Kyujin Shin, Sanggeun Song, Minho Lee, Yeongchang Goh, Mi Hee Lim, Ji-Hyun Kim, Jaeyoung Sung* and Kang Taek Lee*, 
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Abstract

Synaptic vesicle transport by motor proteins along microtubules is a crucially active process underlying neuronal communication. It is known that microtubules are destabilized by tau-hyperphosphorylation, which causes tau proteins to detach from microtubules and form neurofibril tangles. However, how tau-phosphorylation affects the transport dynamics of motor proteins on the microtubule remains unknown. Here, we discover that the long-distance unidirectional motion of vesicle-motor protein multiplexes (VMPMs) in living cells is suppressed under tau-hyperphosphorylation, with the consequent loss of fast vesicle-transport along the microtubule. The VMPMs in hyperphosphorylated cells exhibit seemingly bidirectional random motion, with dynamic properties far different from those of VMPM motion in normal cells. We establish a parsimonious physicochemical model of VMPM’s active motion that provides a unified, quantitative explanation and predictions for our experimental results. Our analysis reveals that, under hyperphosphorylation conditions, motor protein multiplexes have both static and dynamic motility fluctuations. The loss of fast vesicle-transport along the microtubule can be a mechanism of neurodegenerative disorders associated with tau-hyperphosphorylation.

Abstract Image

实时跟踪活细胞中的囊泡发现 Tau 过度磷酸化抑制了马达蛋白的单向运输
运动蛋白沿着微管进行突触囊泡运输是神经元通信的一个关键活跃过程。众所周知,tau过度磷酸化会破坏微管的稳定性,导致tau蛋白脱离微管,形成神经纤维缠结。然而,tau-磷酸化如何影响微管上运动蛋白的运输动力学仍是未知数。在这里,我们发现在活细胞中,囊泡-运动蛋白复合物(VMPMs)的长距离单向运动在tau-过磷酸化作用下受到抑制,从而失去了沿微管的快速囊泡运输。高磷酸化细胞中的VMPM表现出看似双向的随机运动,其动态特性与正常细胞中的VMPM运动大相径庭。我们为 VMPM 的主动运动建立了一个简明的物理化学模型,为我们的实验结果提供了统一的定量解释和预测。我们的分析表明,在过度磷酸化条件下,运动蛋白复合物既有静态波动,也有动态波动。失去沿微管的快速囊泡运输可能是与 tau 过度磷酸化相关的神经退行性疾病的一种机制。
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来源期刊
Chemical & Biomedical Imaging
Chemical & Biomedical Imaging 化学与生物成像-
CiteScore
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期刊介绍: Chemical & Biomedical Imaging is a peer-reviewed open access journal devoted to the publication of cutting-edge research papers on all aspects of chemical and biomedical imaging. This interdisciplinary field sits at the intersection of chemistry physics biology materials engineering and medicine. The journal aims to bring together researchers from across these disciplines to address cutting-edge challenges of fundamental research and applications.Topics of particular interest include but are not limited to:Imaging of processes and reactionsImaging of nanoscale microscale and mesoscale materialsImaging of biological interactions and interfacesSingle-molecule and cellular imagingWhole-organ and whole-body imagingMolecular imaging probes and contrast agentsBioluminescence chemiluminescence and electrochemiluminescence imagingNanophotonics and imagingChemical tools for new imaging modalitiesChemical and imaging techniques in diagnosis and therapyImaging-guided drug deliveryAI and machine learning assisted imaging
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