Excess ribosomal protein production unbalances translation in a model of Fragile X Syndrome

Sang S. Seo, Susana R. Louros, Natasha Anstey, Miguel A. Gonzalez-Lozano, Callista B. Harper, Nicholas C. Verity, Owen Dando, Sophie R. Thomson, Jennifer C. Darnell, Peter C. Kind, Ka Wan Li, Emily K. Osterweil*

*Corresponding author for this work

Research output: Contribution to JournalArticleAcademicpeer-review

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.

Original languageEnglish
Article number3236
Pages (from-to)1-18
Number of pages18
JournalNature Communications
Volume13
DOIs
Publication statusPublished - 10 Jun 2022

Bibliographical 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:
© 2022, The Author(s).

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