title: Peripheral neuropathy via mutant tRNA synthetases: Inhibition of protein translation provides a possible explanation.
abstract: Recent evidence indicates that inhibition of protein translation may be a common pathogenic mechanism for peripheral neuropathy associated with mutant tRNA synthetases (aaRSs). aaRSs are enzymes that ligate amino acids to their cognate tRNA, thus catalyzing the first step of translation. Dominant mutations in five distinct aaRSs cause Charcot-Marie-Tooth (CMT) peripheral neuropathy, characterized by length-dependent degeneration of peripheral motor and sensory axons. Surprisingly, loss of aminoacylation activity is not required for mutant aaRSs to cause CMT. Rather, at least for some mutations, a toxic-gain-of-function mechanism underlies CMT-aaRS. Interestingly, several mutations in two distinct aaRSs were recently shown to inhibit global protein translation in Drosophila models of CMT-aaRS, by a mechanism independent of aminoacylation, suggesting inhibition of translation as a common pathogenic mechanism. Future research aimed at elucidating the molecular mechanisms underlying the translation defect induced by CMT-mutant aaRSs should provide novel insight into the molecular pathogenesis of these incurable diseases.
authors.affiliation: Molecular Neurogenetics Laboratory, Max Planck Institute for Molecular Biomedicine, Münster, Germany.|Faculty of Medicine, University of Münster, Münster, Germany.
authors.forename: Erik
authors.initials: E
authors.lastname: Storkebaum
mesh_terms: D000604:Amino Acyl-tRNA Synthetases / Q000235:genetics*; D000818:Animals; D001369:Axons / Q000378:metabolism; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D006801:Humans; D009154:Mutation
chemical_list: D000604:Amino Acyl-tRNA Synthetases
keywords: Charcot-Marie-Tooth peripheral neuropathy; aminoacylation; animal model; axonal degeneration; gain-of-toxic-function; tRNA synthetase; translation