Sobell Department of Motor Neuroscience and Movement Disorders, Institute of Neurology, University College London, London, WC1N 3BG, UK.
Department of Molecular Medicine, The Scripps Research Institute, La Jolla, California, 92037, USA.
Sci Rep. 2017 Aug 23;7(1):9216. doi: 10.1038/s41598-017-10005-w.
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.
导致 2D 型腓骨肌萎缩症（CMT2D）的管家基因 GARS 中显性遗传突变通过何种机制介导选择性周围神经毒性，目前仍未完全阐明。跨膜受体蛋白神经纤毛蛋白 1（Nrp1）最近被鉴定为突变甘氨酰-tRNA 合成酶（GlyRS）的异常细胞外结合伴侣。Nrp1/突变 GlyRS 复合物的形成拮抗了 Nrp1 与其主要天然配体之一血管内皮生长因子 A（VEGF-A）的相互作用，导致神经退行性变。然而，已知 VEGF-A 与 Nrp1 的细胞外结合减少会破坏出生后血管的发育和生长。因此，我们分析了 CMT2D 小鼠肌肉、视网膜和坐骨神经以及胚胎后脑的早期和晚期症状时间点的血管系统。突变组织在从胚胎发育到三个月的时间内，在血管直径、密度/生长和分支方面没有差异，这一时间段跨越了许多感觉和神经肌肉表型出现的时间。我们的发现表明，突变 GlyRS 介导的 Nrp1/VEGF-A 信号转导中断允许 CMT2D 小鼠的血管成熟和维持。
