Queuosine-tRNA promotes sex-dependent learning and memory formation by maintaining codon-biased translation elongation speed

Cansu Cirzi, Julia Dyckow, Carine Legrand, Johanna Schott, Wei Guo, Daniel Perez Hernandez, Miharu Hisaoka, Rosanna Parlato, Claudia Pitzer, Franciscus van der Hoeven, Gunnar Dittmar, Mark Helm, Georg Stoecklin, Lucas Schirmer, Frank Lyko, Francesca Tuorto*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

7 Citations (Scopus)

Abstract

Queuosine (Q) is a modified nucleoside at the wobble position of specific tRNAs. In mammals, queuosinylation is facilitated by queuine uptake from the gut microbiota and is introduced into tRNA by the QTRT1-QTRT2 enzyme complex. By establishing a Qtrt1 knockout mouse model, we discovered that the loss of Q-tRNA leads to learning and memory deficits. Ribo-Seq analysis in the hippocampus of Qtrt1-deficient mice revealed not only stalling of ribosomes on Q-decoded codons, but also a global imbalance in translation elongation speed between codons that engage in weak and strong interactions with their cognate anticodons. While Q-dependent molecular and behavioral phenotypes were identified in both sexes, female mice were affected more severely than males. Proteomics analysis confirmed deregulation of synaptogenesis and neuronal morphology. Together, our findings provide a link between tRNA modification and brain functions and reveal an unexpected role of protein synthesis in sex-dependent cognitive performance.

Original languageEnglish
Article numbere112507
JournalEMBO Journal
Volume42
Issue number19
Early online date23 Aug 2023
DOIs
Publication statusPublished - 4 Oct 2023

Keywords

  • learning and memory
  • protein translation
  • queuosine
  • sex bias
  • tRNA modifications

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