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

Sang Seo, Susana Ribeiro dos Louros, Natasha Anstey, Miguel A Gonzalez-Lozano, Callista Harper, Nicholas Verity, Owen Dando, Sophie Thomson, Jennifer C Darnell, Peter C Kind, Ka Wan Li, Emily Osterweil

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

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
Number of pages18
JournalNature Communications
Publication statusPublished - 10 Jun 2022


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