CMT2D neuropathy is linked to the neomorphic binding activity of glycyl-tRNA synthetase.
CMT2D neuropathy is linked to the neomorphic binding activity of glycyl-tRNA synthetase.
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DOI：
10.1038/nature15510
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发表时间：
2015-10-29
期刊：
影响因子：
64.8
通讯作者：
Yang XL
中科院分区：
文献类型：
--
作者：
He W;Bai G;Zhou H;Wei N;White NM;Lauer J;Liu H;Shi Y;Dumitru CD;Lettieri K;Shubayev V;Jordanova A;Guergueltcheva V;Griffin PR;Burgess RW;Pfaff SL;Yang XL
选择性神经元丢失是神经退行性疾病的标志，其通常是由广泛表达的基因突变引起的。腓骨肌萎缩症（CMT）是最常见的遗传性周围神经病，目前尚无有效的治疗方法。这种疾病的一个亚型-CMT 2D-是由编码广泛表达的甘氨酰-tRNA合成酶（GlyRS）的加尔斯显性突变引起的。尽管GlyRS对所有细胞中的蛋白质生物合成具有广泛的需求，但该基因的突变导致外周轴突的选择性变性，从而导致远端运动功能的缺陷。GlyRS（GlyRSCMT 2D）突变如何与运动神经元脆弱性联系在一起仍然难以捉摸。在这里，我们报告说，GlyRSCMT 2D获得一个neomorphic结合活性，直接拮抗运动神经元存活的一个重要信号通路。我们发现CMT 2D突变改变了GlyRS的构象，使GlyRSCMT 2D能够结合神经纤毛蛋白1（Nrp 1）受体。这种异常的相互作用竞争性地干扰同源配体血管内皮生长因子（VEGF）与Nrp 1的结合。小鼠中Nrp 1的遗传减少减轻了CMT 2D症状，而VEGF的表达增强改善了运动功能。这些发现将CMT 2D的选择性病理学与GlyRSCMT 2D的新形态结合活性联系起来，GlyRSCMT 2D拮抗VEGF/Nrp 1相互作用，并表明VEGF/Nrp 1信号传导轴是治疗CMT 2D的可行靶点。
Selective neuronal loss is a hallmark of neurodegenerative diseases, which counter-intuitively 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 the diseases—CMT2D—is caused by dominant mutations in GARS, encoding the ubiquitously expressed enzyme glycyl-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 (GlyRSCMT2D) are linked to motor neuron vulnerability has remained elusive. Here we report that GlyRSCMT2D acquires a neomorphic binding activity that directly antagonizes an essential signaling pathway for motor neuron survival. We find that CMT2D mutations alter the conformation of GlyRS, enabling GlyRSCMT2D 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 GlyRSCMT2D that antagonizes the VEGF/Nrp1 interaction, and indicate the VEGF/Nrp1 signaling axis is an actionable target for treating CMT2D.