Oligodendrocyte differentiation alters tRNA modifications and codon optimality-mediated mRNA decay

Sophie Martin, Kevin C. Allan, Otis Pinkard, Thomas Sweet, Paul J. Tesar and Jeff Coller ()
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Sophie Martin: Johns Hopkins University School of Medicine
Kevin C. Allan: Case Western Reserve University School of Medicine
Otis Pinkard: Case Western Reserve University School of Medicine
Thomas Sweet: Case Western Reserve University School of Medicine
Paul J. Tesar: Case Western Reserve University School of Medicine
Jeff Coller: Johns Hopkins University School of Medicine

Nature Communications, 2022, vol. 13, issue 1, 1-21

Abstract: Abstract Oligodendrocytes are specialized cells that confer neuronal myelination in the central nervous system. Leukodystrophies associated with oligodendrocyte deficits and hypomyelination are known to result when a number of tRNA metabolism genes are mutated. Thus, for unknown reasons, oligodendrocytes may be hypersensitive to perturbations in tRNA biology. In this study, we survey the tRNA transcriptome in the murine oligodendrocyte cell lineage and find that specific tRNAs are hypomodified in oligodendrocytes within or near the anticodon compared to oligodendrocyte progenitor cells (OPCs). This hypomodified state may be the result of differential expression of key modification enzymes during oligodendrocyte differentiation. Moreover, we observe a concomitant relationship between tRNA hypomodification and tRNA decoding potential; observing oligodendrocyte specific alterations in codon optimality-mediated mRNA decay and ribosome transit. Our results reveal that oligodendrocytes naturally maintain a delicate, hypersensitized tRNA/mRNA axis. We suggest this axis is a potential mediator of pathology in leukodystrophies and white matter disease when further insult to tRNA metabolism is introduced.

Date: 2022
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DOI: 10.1038/s41467-022-32766-3

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