@article{f66c3e90d58943d68fd4e16839cd28ac,
title = "Excess ribosomal protein production unbalances translation in a model of Fragile X Syndrome",
abstract = "Dysregulated protein synthesis is a core pathogenic mechanism in Fragile X Syndrome (FX). The mGluR Theory of FX predicts that pathological synaptic changes arise from the excessive translation of mRNAs downstream of mGlu1/5 activation. Here, we use a combination of CA1 pyramidal neuron-specific TRAP-seq and proteomics to identify the overtranslating mRNAs supporting exaggerated mGlu1/5 -induced long-term synaptic depression (mGluR-LTD) in the FX mouse model (Fmr1−/y). Our results identify a significant increase in the translation of ribosomal proteins (RPs) upon mGlu1/5 stimulation that coincides with a reduced translation of long mRNAs encoding synaptic proteins. These changes are mimicked and occluded in Fmr1−/y neurons. Inhibiting RP translation significantly impairs mGluR-LTD and prevents the length-dependent shift in the translating population. Together, these results suggest that pathological changes in FX result from a length-dependent alteration in the translating population that is supported by excessive RP translation.",
author = "Sang Seo and {Ribeiro dos Louros}, Susana and Natasha Anstey and Gonzalez-Lozano, {Miguel A} and Callista Harper and Nicholas Verity and Owen Dando and Sophie Thomson and Darnell, {Jennifer C} and Kind, {Peter C} and Li, {Ka Wan} and Emily Osterweil",
note = "Funding Information: Special thanks to David JA Wyllie for help overseeing LTD recordings, and to Katherine Bonnycastle and Mike A Cousin for providing excellent advice for the project. Thanks to Serena Linley-Adams, Katy Homyer, Keiron Scrimger, and Hannah Wat for help with image analysis. Confocal imaging and IMARIS reconstruction were performed in collaboration with the IMPACT facility at the University of Edinburgh. This work was supported by grants from the Wellcome Trust/Royal Society (E.K.O.: SHDF 104116/Z/14/Z and SRF 219556/Z/19/Z), Medical Research Council (E.K.O.: MRC MR/M006336/1 and MR/S026312/1), and Simons Initiative for the Developing Brain (E.K.O.: SIDB). For the purpose of open access, the author has applied a Creative Commons Attribution (CC BY) license to any Author Accepted Manuscript version arising from this submission. Publisher Copyright: {\textcopyright} 2022, The Author(s).",
year = "2022",
month = jun,
day = "10",
doi = "10.1038/s41467-022-30979-0",
language = "English",
volume = "13",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",
}