Neuropilin 1 sequestration by neuropathogenic mutant glycyl-tRNA synthetase is permissive to vascular homeostasis
Abstract The mechanism by which dominantly inherited mutations in the housekeeping gene GARS, which encodes glycyl-tRNA synthetase (GlyRS), mediate selective peripheral nerve toxicity resulting in Charcot-Marie-Tooth disease type 2D (CMT2D) is still largely unresolved. The transmembrane receptor pro...
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| Format: | Article |
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Nature Portfolio
2017-08-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-017-10005-w |
| _version_ | 1823971165648977920 |
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| author | James N. Sleigh Adriana Gómez-Martín Na Wei Ge Bai Xiang-Lei Yang Giampietro Schiavo |
| author_facet | James N. Sleigh Adriana Gómez-Martín Na Wei Ge Bai Xiang-Lei Yang Giampietro Schiavo |
| author_sort | James N. Sleigh |
| collection | DOAJ |
| description | Abstract The mechanism by which dominantly inherited mutations in the housekeeping gene GARS, which encodes glycyl-tRNA synthetase (GlyRS), mediate selective peripheral nerve toxicity resulting in Charcot-Marie-Tooth disease type 2D (CMT2D) is still largely unresolved. The transmembrane receptor protein neuropilin 1 (Nrp1) was recently identified as an aberrant extracellular binding partner of mutant GlyRS. Formation of the Nrp1/mutant GlyRS complex antagonises Nrp1 interaction with one of its main natural ligands, vascular endothelial growth factor-A (VEGF-A), contributing to neurodegeneration. However, reduced extracellular binding of VEGF-A to Nrp1 is known to disrupt post-natal blood vessel development and growth. We therefore analysed the vascular system at early and late symptomatic time points in CMT2D mouse muscles, retina, and sciatic nerve, as well as in embryonic hindbrain. Mutant tissues show no difference in blood vessel diameter, density/growth, and branching from embryonic development to three months, spanning the duration over which numerous sensory and neuromuscular phenotypes manifest. Our findings indicate that mutant GlyRS-mediated disruption of Nrp1/VEGF-A signalling is permissive to maturation and maintenance of the vasculature in CMT2D mice. |
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| format | Article |
| id | doaj.art-de8e9fb7f31545f992c90a302df4673a |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-12-18T03:23:31Z |
| publishDate | 2017-08-01 |
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| record_format | Article |
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| spelling | doaj.art-de8e9fb7f31545f992c90a302df4673a2022-12-21T21:22:42ZengNature PortfolioScientific Reports2045-23222017-08-017111110.1038/s41598-017-10005-wNeuropilin 1 sequestration by neuropathogenic mutant glycyl-tRNA synthetase is permissive to vascular homeostasisJames N. Sleigh0Adriana Gómez-Martín1Na Wei2Ge Bai3Xiang-Lei Yang4Giampietro Schiavo5Sobell Department of Motor Neuroscience and Movement Disorders, Institute of Neurology, University College LondonSobell Department of Motor Neuroscience and Movement Disorders, Institute of Neurology, University College LondonDepartment of Molecular Medicine, The Scripps Research InstituteDepartment of Molecular Medicine, The Scripps Research InstituteDepartment of Molecular Medicine, The Scripps Research InstituteSobell Department of Motor Neuroscience and Movement Disorders, Institute of Neurology, University College LondonAbstract The mechanism by which dominantly inherited mutations in the housekeeping gene GARS, which encodes glycyl-tRNA synthetase (GlyRS), mediate selective peripheral nerve toxicity resulting in Charcot-Marie-Tooth disease type 2D (CMT2D) is still largely unresolved. The transmembrane receptor protein neuropilin 1 (Nrp1) was recently identified as an aberrant extracellular binding partner of mutant GlyRS. Formation of the Nrp1/mutant GlyRS complex antagonises Nrp1 interaction with one of its main natural ligands, vascular endothelial growth factor-A (VEGF-A), contributing to neurodegeneration. However, reduced extracellular binding of VEGF-A to Nrp1 is known to disrupt post-natal blood vessel development and growth. We therefore analysed the vascular system at early and late symptomatic time points in CMT2D mouse muscles, retina, and sciatic nerve, as well as in embryonic hindbrain. Mutant tissues show no difference in blood vessel diameter, density/growth, and branching from embryonic development to three months, spanning the duration over which numerous sensory and neuromuscular phenotypes manifest. Our findings indicate that mutant GlyRS-mediated disruption of Nrp1/VEGF-A signalling is permissive to maturation and maintenance of the vasculature in CMT2D mice.https://doi.org/10.1038/s41598-017-10005-w |
| spellingShingle | James N. Sleigh Adriana Gómez-Martín Na Wei Ge Bai Xiang-Lei Yang Giampietro Schiavo Neuropilin 1 sequestration by neuropathogenic mutant glycyl-tRNA synthetase is permissive to vascular homeostasis Scientific Reports |
| title | Neuropilin 1 sequestration by neuropathogenic mutant glycyl-tRNA synthetase is permissive to vascular homeostasis |
| title_full | Neuropilin 1 sequestration by neuropathogenic mutant glycyl-tRNA synthetase is permissive to vascular homeostasis |
| title_fullStr | Neuropilin 1 sequestration by neuropathogenic mutant glycyl-tRNA synthetase is permissive to vascular homeostasis |
| title_full_unstemmed | Neuropilin 1 sequestration by neuropathogenic mutant glycyl-tRNA synthetase is permissive to vascular homeostasis |
| title_short | Neuropilin 1 sequestration by neuropathogenic mutant glycyl-tRNA synthetase is permissive to vascular homeostasis |
| title_sort | neuropilin 1 sequestration by neuropathogenic mutant glycyl trna synthetase is permissive to vascular homeostasis |
| url | https://doi.org/10.1038/s41598-017-10005-w |
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