tRNA-sequestration as an underlying molecular mechanism of tyrosyl-tRNA synthetase-associated DI-CMTC pathology

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Aminoacyl-tRNA-synthetases (aaRS) are pivotal for protein translation; they aminoacylate tRNAs with cognate amino acid. Heterozygous mutations in six distinct AARSs are connected to devastating dominantly inherited Charcot-Marie-Tooth (CMT) peripheral neuropathies, which is characterized by degeneration of peripheral motor and sensory axons, leading to progressive muscle weakness and wasting and sensory dysfunction. The underlying molecular mechanisms of different CMT forms and their tissue-specific effect remain poorly understood. We recently reported a novel mechanism underlying the CMT2D pathology linked to mutations in the glycyl-tRNA synthetase (GARS), a class II aaRS. The CMT-mutant forms of GARS tightly bind the cognate tRNAs and fail to release them, thus, depleting glycyl-tRNAGly for translation and consequently causing ribosome stalling at Gly codons. Heterozygous mutations in YARS are causal to DI-CMTC pathology. By analysing the kinetics of tRNA binding and release of CMT-mutant tyrosyl-tRNA-synthetase (YARS) variants in Drosophila and mouse CMT models (YarsE196K mice), combined with cell-wide analysis of translation speed and expression, we will determine the molecular mechanism of another class I aaRS associated with CMT pathologies. We expect that this multilayered approach will reveal insights into common and distinct mechanistic facets of mutations in class I and class II aaRSs with a causal link to CMT pathologies.