Department of Bioengineering, McGill University, Montréal, Quebec, Canada.
Laboratory of Sensory Neuroscience, The Rockefeller University, New York, New York.
Traffic. 2018 Feb;19(2):111-121. doi: 10.1111/tra.12537. Epub 2017 Dec 5.
Organelles, proteins, and mRNA are transported bidirectionally along microtubules by plus-end directed kinesin and minus-end directed dynein motors. Microtubules are decorated by microtubule-associated proteins (MAPs) that organize the cytoskeleton, regulate microtubule dynamics and modulate the interaction between motor proteins and microtubules to direct intracellular transport. Tau is a neuronal MAP that stabilizes axonal microtubules and crosslinks them into bundles. Dysregulation of tau leads to a range of neurodegenerative diseases known as tauopathies including Alzheimer's disease (AD). Tau reduces the processivity of kinesin and dynein by acting as an obstacle on the microtubule. Single-molecule assays indicate that kinesin-1 is more strongly inhibited than kinesin-2 or dynein, suggesting tau might act to spatially modulate the activity of specific motors. To investigate the role of tau in regulating bidirectional transport, we isolated phagosomes driven by kinesin-1, kinesin-2, and dynein and reconstituted their motility along microtubules. We find that tau biases bidirectional motility towards the microtubule minus-end in a dose-dependent manner. Optical trapping measurements show that tau increases the magnitude and frequency of forces exerted by dynein through inhibiting opposing kinesin motors. Mathematical modeling indicates that tau controls the directional bias of intracellular cargoes through differentially tuning the processivity of kinesin-1, kinesin-2, and dynein. Taken together, these results demonstrate that tau modulates motility in a motor-specific manner to direct intracellular transport, and suggests that dysregulation of tau might contribute to neurodegeneration by disrupting the balance of plus- and minus-end directed transport.
细胞器、蛋白质和 mRNA 沿着微管双向运输，由正向驱动的驱动蛋白和负向驱动的动力蛋白驱动。微管由微管相关蛋白（MAPs）装饰，这些蛋白组织细胞骨架，调节微管动力学，并调节马达蛋白与微管之间的相互作用，以指导细胞内运输。Tau 是一种神经元 MAP，可稳定轴突微管并将其交联成束。Tau 的失调导致一系列称为 tau 病的神经退行性疾病，包括阿尔茨海默病（AD）。Tau 通过在微管上充当障碍物来降低驱动蛋白和动力蛋白的连续性。单分子测定表明，与 kinesin-2 或 dynein 相比，kinesin-1 的抑制作用更强，这表明 Tau 可能起到空间调节特定马达活性的作用。为了研究 Tau 在调节双向运输中的作用，我们分离了由 kinesin-1、kinesin-2 和 dynein 驱动的吞噬体，并重建了它们沿微管的运动。我们发现 Tau 以剂量依赖的方式将双向运动偏向微管的负端。光学捕获测量表明，Tau 通过抑制相反的驱动蛋白马达来增加 dynein 施加的力的幅度和频率。数学模型表明，Tau 通过差异调节 kinesin-1、kinesin-2 和 dynein 的连续性来控制细胞内货物的定向偏差。总之，这些结果表明 Tau 以特定于马达的方式调节运动，以指导细胞内运输，并表明 Tau 的失调可能通过破坏正向和负向运输的平衡导致神经退行性变。
