CMT2D neuropathy is linked to the neomorphic binding activity of glycyl-tRNA synthetase

• Published in: Nature (London) 2015-10, Vol.526 (7575), p.710-714
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: 101/58; 14/1; 14/19; 14/34; 14/35; 14/63; 38/109; 38/22; 42/44; 631/208/2490; 631/378/1689/364; 631/45/607; 631/535; 631/80/304; 64/60; Aminoacyl-tRNA synthetases; Analysis; Animals; Axons - enzymology; Axons - metabolism; Axons - pathology; Binding, Competitive; Biosynthesis; Cell Line; Cell Survival; Charcot-Marie-Tooth disease; Charcot-Marie-Tooth Disease - drug therapy; Charcot-Marie-Tooth Disease - genetics; Charcot-Marie-Tooth Disease - metabolism; Charcot-Marie-Tooth Disease - pathology; Diagnosis; Enzyme binding; Enzymes; Female; Genes; Genetic aspects; Glycine-tRNA Ligase - chemistry; Glycine-tRNA Ligase - genetics; Glycine-tRNA Ligase - metabolism; Humanities and Social Sciences; letter; Ligands; Male; Mice; Models, Molecular; Motor Neurons - enzymology; Motor Neurons - metabolism; Motor Neurons - pathology; Motor Skills - drug effects; multidisciplinary; Mutation; Mutation - genetics; Nervous system; Neurodegeneration; Neurons; Neuropathology; Neuropilin-1 - deficiency; Neuropilin-1 - genetics; Neuropilin-1 - metabolism; Physiological aspects; Protein Binding; Protein Multimerization; Proteins; Science; Signal Transduction; Transfer RNA; Vascular Endothelial Growth Factor A - metabolism; Vascular Endothelial Growth Factor A - pharmacology; Vascular Endothelial Growth Factor A - therapeutic use
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature15510

Charcot–Marie–Tooth diseases are hereditary peripheral neuropathies for which there are currently no effective therapies; here the type 2D subtype of these diseases is shown to be caused by mutations impeding a signalling pathway necessary for motor neuron survival. Neuropathy link to VEGF–Nrp1 signalling defect Charcot–Marie–Tooth diseases are hereditary peripheral neuropathies for which there are currently no effective therapies. The type 2D subtype of these diseases (CMT2D) is associated with dominant mutations in the enzyme glycyl-tRNA synthetase (GlyRS). Here the molecular mechanism by which these mutations cause neuropathy is shown to involve suppression of a signalling pathway necessary for motor neuron survival. CMT2D mutations alter the conformation of GlyRS, enabling it 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, and indicates that the VEGF–Nrp1 signalling axis is an actionable target for treating CMT2D. Selective neuronal loss is a hallmark of neurodegenerative diseases, which, counterintuitively, are often caused by mutations in widely expressed genes 1 . Charcot–Marie–Tooth (CMT) diseases are the most common hereditary peripheral neuropathies, for which there are no effective therapies 2 , 3 . 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 4 . 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 ant