Aminoacyl-tRNA synthetase organization is crucial for mammalian brain development

Abstract

Central nervous system development relies on spatially regulated protein synthesis, which includes the aminoacylation of tRNAs. Developmental brain disorders, such as leukodystrophies, can be caused by the exclusion of Arginyl-tRNA synthetase (RARS1) from the multi-tRNA synthetase complex, which does not affect its enzymatic function. To understand the purpose of aminoacyl-tRNA synthetase complex formation, we engineered a mouse line where RARS1 is untethered from the complex in forebrains. We observed profound behavioral phenotypes and anatomical changes originating from a severe reduction in oligodendrocytes and subsequent myelination defects. On the molecular level, disruption of the multi-tRNA synthetase complex caused RARS1 mis-trafficking, which resulted in lost colocalization with ribosomes, leading to the concomitant activation of integrated stress response. Proteomics analysis of newly synthesized proteins suggested that mRNA translation in cellular projections was specifically reduced, affecting myelin structural proteins. In summary, exclusion of RARS1 from the multisynthetase complex led to its altered subcellular localization and decreased protein synthesis in oligodendrocyte projections, directly linking molecular effects to white matter pathologies. Altogether, our results reveal the necessity of aminoacylation organization for mammalian neurodevelopment.

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