Search

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. [ABSTRACT FROM AUTHOR]

Endonuclease‐mediated tRNA fragmentation has been observed in many species suggesting functional importance for tRNA fragments. The size distribution of tRNA‐derived fragments indicates the existence of mechanisms that protect tRNAs and their fragments from total degradation by exonucleases. Could post‐transcriptional modifications be important for the controlled processing of tRNAs? [ABSTRACT FROM AUTHOR]