National Academy of Sciences, Proceedings of the National Academy of Sciences, 13(118), 2021
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Significance Charcot-Marie-Tooth disease (CMT) is a devastating motor and sensory neuropathy with an estimated 100,000 afflicted individuals in the US. Unexpectedly, aminoacyl-tRNA synthetases are the largest disease-associated protein family. A natural explanation is that the disease is associated with weak translation or mistranslation (caused by editing defects). However, our results with six different disease-causing mutants in AlaRS ruled out defects in aminoacylation or editing as causal factors. Instead, specific mutant proteins gained a neuropilin 1 (Nrp1)-AlaRS interaction. Previously a gain of Nrp1 interaction with a different disease-causing tRNA synthetase was mechanistically linked to the pathology of CMT. Thus, our results raise the possibility that pathological engagement of Nrp1 is common to at least a subset of tRNA synthetase-associated cases of CMT.