Publication Date:
2015-10-28
Description:
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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4754353/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4754353/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉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 -- R01 GM088278/GM/NIGMS NIH HHS/ -- R01 NS037116/NS/NINDS NIH HHS/ -- R01 NS054154/NS/NINDS NIH HHS/ -- R01 NS054172/NS/NINDS NIH HHS/ -- R01GM088278/GM/NIGMS NIH HHS/ -- R01NS054154/NS/NINDS NIH HHS/ -- R21 NS084254/NS/NINDS NIH HHS/ -- R21NS084254/NS/NINDS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2015 Oct 29;526(7575):710-4. doi: 10.1038/nature15510. Epub 2015 Oct 21.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉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. ; Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, Florida 33458, USA. ; Department of Anesthesiology, University of California San Diego, La Jolla, California 92093, USA. ; Molecular Neurogenomics Group, VIB Department of Molecular Genetics, University of Antwerp, BE-2610 Antwerp, Belgium. ; Department of Neurology, Medical University of Sofia, 1431 Sofia, Bulgaria. ; The Jackson Laboratory, Bar Harbor, Maine 04609, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26503042" target="_blank"〉PubMed〈/a〉
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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