Department of Biological Sciences, The State University of New York at Buffalo, Buffalo, NY 14260, USA.
Hum Mol Genet. 2018 Sep 1;27(17):2986-3001. doi: 10.1093/hmg/ddy190.
Neurons require intracellular transport of essential components for function and viability and defects in transport has been implicated in many neurodegenerative diseases including Alzheimer's disease (AD). One possible mechanism by which transport defects could occur is by improper regulation of molecular motors. Previous work showed that reduction of presenilin (PS) or glycogen synthase kinase 3 beta (GSK3β) stimulated amyloid precursor protein vesicle motility. Excess GSK3β caused transport defects and increased motor binding to membranes, while reduction of PS decreased active GSK3β and motor binding to membranes. Here, we report that functional PS and the catalytic loop region of PS is essential for the rescue of GSK3β-mediated axonal transport defects. Disruption of PS loop (PSΔE9) or expression of the non-functional PS variant, PSD447A, failed to rescue axonal blockages in vivo. Further, active GSK3β associated with and phosphorylated kinesin-1 in vitro. Our observations together with previous work that showed that the loop region of PS interacts with GSK3β propose a scaffolding mechanism for PS in which the loop region sequesters GSK3β away from motors for the proper regulation of motor function. These findings are important to uncouple the complex regulatory mechanisms that likely exist for motor activity during axonal transport in vivo.
神经元需要细胞内运输必要的成分才能发挥功能和维持生存，而运输缺陷与许多神经退行性疾病有关，包括阿尔茨海默病（AD）。运输缺陷可能发生的一种机制是分子马达的调节不当。先前的研究表明，降低早老素（PS）或糖原合酶激酶 3β（GSK3β）可刺激淀粉样前体蛋白囊泡的运动。过量的 GSK3β 会导致运输缺陷，并增加马达与膜的结合，而 PS 的减少会降低活性 GSK3β 和马达与膜的结合。在这里，我们报告功能 PS 和 PS 的催化环区对于挽救 GSK3β 介导的轴突运输缺陷是必不可少的。PS 环的破坏（PSΔE9）或非功能 PS 变体 PSD447A 的表达均未能在体内挽救 GSK3β 引起的轴突阻断。此外，活性 GSK3β 在体外与驱动蛋白-1 结合并使其磷酸化。我们的观察结果与先前的工作一起表明，PS 的环区与 GSK3β 相互作用，提出了 PS 的支架机制，其中环区将 GSK3β 隔离在远离马达的地方，以正确调节马达的功能。这些发现对于解开体内轴突运输中可能存在的复杂的马达活性调控机制具有重要意义。
