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

Charcot-Marie-Tooth (CMT) diseases are the most common family of inherited diseases called peripheral neuropathies. The junctions between muscles and nerves and the nerves themselves that carry signals between brain and muscles degenerate over time, leading to impaired movement, including balance problems and difficulty walking. CMT diseases have a range of severity but are rarely life-threatening.

A collaborative research group, led by Xiang-Lei Yang of The Scripps Research Institute and including Professor Rob Burgess of JAX, investigated a subset of CMT cases caused by mutations in a gene called GARS, and their findings were published in Nature on October 21. GARS encodes a kind of protein known as a tRNA synthetase, which is involved in making other proteins. Interestingly, this protein (GlyRS) is required to make proteins in all cells, but the mutations only affect the peripheral nerve cells, causing degeneration and the movement problems characteristic of CMT.

Since GlyRS still performs its essential function despite the CMT mutations, the scientists suspected that the mutations caused it to also gain another, damaging function. And that’s what they found. The mutant GlyRS protein’s structure is altered, and it they found that it binds a receptor on the surface of the peripheral nerve cells in its altered state. The receptor, known as Nrp1, is supposed to bind a growth factor that is part of a signaling pathway essential for nerve cell survival. If GlyRS binds to it instead, the nerve cell degenerates and dies. The finding provides both a plausible disease mechanism and a potential target for improved therapies.