Department of Neurobiology, Harvard Medical School, Boston, MA.
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA.
J Cell Biol. 2021 Jan 4;220(1). doi: 10.1083/jcb.202005051.
Complex neural circuitry requires stable connections formed by lengthy axons. To maintain these functional circuits, fast transport delivers RNAs to distal axons where they undergo local translation. However, the mechanism that enables long-distance transport of RNA granules is not yet understood. Here, we demonstrate that a complex containing RNA and the RNA-binding protein (RBP) SFPQ interacts selectively with a tetrameric kinesin containing the adaptor KLC1 and the motor KIF5A. We show that the binding of SFPQ to the KIF5A/KLC1 motor complex is required for axon survival and is impacted by KIF5A mutations that cause Charcot-Marie Tooth (CMT) disease. Moreover, therapeutic approaches that bypass the need for local translation of SFPQ-bound proteins prevent axon degeneration in CMT models. Collectively, these observations indicate that KIF5A-mediated SFPQ-RNA granule transport may be a key function disrupted in KIF5A-linked neurologic diseases and that replacing axonally translated proteins serves as a therapeutic approach to axonal degenerative disorders.
复杂的神经回路需要由长轴突形成的稳定连接。为了维持这些功能性回路，快速运输将 RNA 运送到远端轴突，在那里它们进行局部翻译。然而，RNA 颗粒长距离运输的机制尚不清楚。在这里，我们证明了一种包含 RNA 和 RNA 结合蛋白 (RBP) SFPQ 的复合物与包含接头 KLC1 和马达蛋白 KIF5A 的四聚体驱动蛋白选择性结合。我们表明，SFPQ 与 KIF5A/KLC1 马达复合物的结合对于轴突存活是必需的，并且受到导致遗传性运动感觉神经病（CMT）的 KIF5A 突变的影响。此外，绕过 SFPQ 结合蛋白局部翻译的治疗方法可防止 CMT 模型中的轴突退化。总之，这些观察结果表明，KIF5A 介导的 SFPQ-RNA 颗粒运输可能是 KIF5A 相关神经疾病中破坏的关键功能，并且替代轴突翻译的蛋白质是轴突退行性疾病的一种治疗方法。
