Charcot-Marie-Tooth (CMT) disease, also known as hereditary motor and sensory neuropathy, is one of the most common inherited neurological disorders, affecting approximately 1 in 2500 people in the US. Mutations in glycyl-transfer RNA synthetase (GlyRS) are known to cause one subtype of CMT, but how this ubiquitously expressed protein leads to selective degeneration of peripheral axons has been unclear. In the October 29th Nature, researchers led by Samuel Pfaff at the Salk Institute and Xiang-Lei Yang of The Scripps Research Institute in La Jolla, CA, describe a potential mechanism that could underlie this selective vulnerability. The researchers report that GlyRS-mutant enzymes bind to the transmembrane receptor neuropilin 1 (Nrp1) in motor neurons and inhibit binding of vascular endothelial growth factor (VEGF) to these receptors, thereby blocking a key pathway for motor neuron survival. Increasing VEGF expression improved muscle strength in a CMT2D mouse model, while genetic reduction of Nrp1 exacerbated the CMT phenotype in mice. These findings point to a critical pathway that contributes to selective neuronal death in CMT, and could present a new avenue for targeted therapies.
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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. CMT2D neuropathy is linked to the neomorphic binding activity of glycyl-tRNA synthetase. Nature. 2015 Oct 29;526(7575):710-4. [Pubmed].