He Weiwei, Bai Ge, Zhou Huihao, Wei Na, White Nicholas M, Lauer Janelle, Liu Huaqing, Shi Yi, Dumitru Calin Dan, Lettieri Karen, Shubayev Veronica, Jordanova Albena, Guergueltcheva Velina, Griffin Patrick R, Burgess Robert W, Pfaff Samuel L, Yang Xiang-Lei
Departments of Chemical Physiology and Cell and Molecular Biology, The Scripps Research Institute, La Jolla, California 92037, USA.
Howard Hughes Medical Institute and Gene Expression Laboratory, The Salk Institute for Biological Studies, La Jolla, California 92037, USA.
Nature. 2015 Oct 29;526(7575):710-4. doi: 10.1038/nature15510. Epub 2015 Oct 21.
Selective neuronal loss is a hallmark of neurodegenerative diseases, which, counterintuitively, are often caused by mutations in widely expressed genes. Charcot-Marie-Tooth (CMT) diseases are the most common hereditary peripheral neuropathies, for which there are no effective therapies. A subtype of these diseases--CMT type 2D (CMT2D)--is caused by dominant mutations in GARS, encoding the ubiquitously expressed enzyme glycyl-transfer RNA (tRNA) synthetase (GlyRS). Despite the broad requirement of GlyRS for protein biosynthesis in all cells, mutations in this gene cause a selective degeneration of peripheral axons, leading to deficits in distal motor function. How mutations in GlyRS (GlyRS(CMT2D)) are linked to motor neuron vulnerability has remained elusive. Here we report that GlyRS(CMT2D) acquires a neomorphic binding activity that directly antagonizes an essential signalling pathway for motor neuron survival. We find that CMT2D mutations alter the conformation of GlyRS, enabling GlyRS(CMT2D) to bind the neuropilin 1 (Nrp1) receptor. This aberrant interaction competitively interferes with the binding of the cognate ligand vascular endothelial growth factor (VEGF) to Nrp1. Genetic reduction of Nrp1 in mice worsens CMT2D symptoms, whereas enhanced expression of VEGF improves motor function. These findings link the selective pathology of CMT2D to the neomorphic binding activity of GlyRS(CMT2D) that antagonizes the VEGF-Nrp1 interaction, and indicate that the VEGF-Nrp1 signalling axis is an actionable target for treating CMT2D.
选择性神经元丢失是神经退行性疾病的一个标志，而与直觉相反的是，这些疾病通常是由广泛表达的基因发生突变引起的。夏科-马里-图斯（CMT）病是最常见的遗传性周围神经病，目前尚无有效的治疗方法。这些疾病的一个亚型——CMT2D型（CMT2D）——是由GARS基因的显性突变引起的，该基因编码普遍表达的甘氨酰转移RNA（tRNA）合成酶（GlyRS）。尽管GlyRS在所有细胞的蛋白质生物合成中都有广泛需求，但该基因的突变会导致外周轴突选择性退化，进而导致远端运动功能缺陷。GlyRS（GlyRS(CMT2D)）中的突变如何与运动神经元易损性相关联，一直难以捉摸。在这里，我们报告GlyRS(CMT2D)获得了一种新的结合活性，该活性直接拮抗运动神经元存活所必需的信号通路。我们发现，CMT2D突变改变了GlyRS的构象，使GlyRS(CMT2D)能够结合神经纤毛蛋白1（Nrp1）受体。这种异常相互作用竞争性地干扰了同源配体血管内皮生长因子（VEGF）与Nrp1的结合。小鼠中Nrp1基因表达降低会使CMT2D症状恶化，而VEGF表达增强则可改善运动功能。这些发现将CMT2D的选择性病理与GlyRS(CMT2D)拮抗VEGF-Nrp1相互作用的新结合活性联系起来，并表明VEGF-Nrp1信号轴是治疗CMT2D的一个可行靶点。
