부산대학교 도서관

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. Synopsis: Queuosine (Q) is a modified nucleoside introduced in specific tRNAs by a complex comprising queuine tRNA ribosyltransferase 1 (QTRT1). Loss of Q‐tRNA modification by the knockout of Qtrt1 gene in mice (Q1) leads to an imbalance in codon‐biased protein translation speed, resulting in alterations of hippocampal architecture and sex‐dependent reduction in learning and memory formation.Q‐tRNA levels vary considerably between murine tissues, with the brain showing a high queuosinylation level.Loss of Q results in learning and memory deficits, with females being more affected than male mice.Q1 mice exhibit altered neuronal cytoarchitecture in the hippocampus.Loss of Q leads to ribosome stalling on Q‐decoded codons and alteration of overall protein translation homeostasis.Translational stress and increased eIF2α phosphorylation impair neuronal cognitive functions in Q1 female mice. [ABSTRACT FROM AUTHOR]