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

The EMBO Journal · 16 authors, 14 centres

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Wild-type female mice outperformed males in behavioral tests, but the loss of Q modification eliminated this female advantage.

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The authors generated a tissue-specific Q-tRNA atlas showing highest levels in heart, skeletal muscle, and brain, and lowest in spleen. These translational changes were associated with alterations in hippocampal cellular architecture, including loss of Syt1- and NeuN-expressing neurons and dendritic arborization changes. eIF2 signaling was deregulated, consistent with ribosome stalling-induced eIF2α phosphorylation. Wild-type female mice outperformed males across behavioral tests, but Q deficiency abolished this female advantage.

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other

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neurology

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ORIGINAL PAPER

PMC10548180

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

The EMBO Journal

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ABSTRACT

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. Keywords: learning and memory, protein translation, queuosine, sex bias, tRNA modifications Subject Categories: Neuroscience, RNA Biology

CITATION EXPORT

Cansu Cirzi, Julia Dyckow, Carine Legrand et al.. Queuosine‐tRNA promotes sex‐dependent learning and memory formation by maintaining codon‐biased translation elongation speed. The EMBO Journal. (2023). https://doi.org/10.15252/embj.2022112507

AUTHORS

16 · 14 CENTRES

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

1 Division of Epigenetics, DKFZ‐ZMBH Alliance, German Cancer Research Center (DKFZ), Heidelberg, Germany
2 Faculty of Biosciences, Heidelberg University, Heidelberg, Germany
3 Department of Neurology, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
4 Interdisciplinary Center for Neurosciences, Heidelberg University, Heidelberg, Germany
5 Université Paris Cité, Génomes, Biologie Cellulaire et Thérapeutique U944, INSERM, CNRS, Paris, France
6 Center for Molecular Biology of Heidelberg University (ZMBH), DKFZ‐ZMBH Alliance, Heidelberg, Germany
7 Division of Biochemistry, Mannheim Institute for Innate Immunoscience (MI3), Mannheim Cancer Center (MCC), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
8 Department of Infection and Immunity, Luxembourg Institute of Health, Strassen, Luxembourg
9 Division of Neurodegenerative Disorders, Department of Neurology, Medical Faculty Mannheim, Mannheim Center for Translational Neurosciences, Heidelberg University, Mannheim, Germany
10 Interdisciplinary Neurobehavioral Core (INBC), Medical Faculty Heidelberg, Heidelberg University, Heidelberg, Germany
11 Transgenic Service W450, German Cancer Research Center (DKFZ), Heidelberg, Germany
12 Department of Life Sciences and Medicine, University of Luxembourg, Luxembourg
13 Institute of Pharmaceutical and Biomedical Science (IPBS), Johannes Gutenberg‐University Mainz, Mainz, Germany
14 Mannheim Center for Translational Neuroscience and Institute for Innate Immunoscience, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany