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 and Emily K. Osterweil ()
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Sang S. Seo: University of Edinburgh
Susana R. Louros: University of Edinburgh
Natasha Anstey: University of Edinburgh
Miguel A. Gonzalez-Lozano: Vrije Universiteit Amsterdam
Callista B. Harper: University of Edinburgh
Nicholas C. Verity: University of Edinburgh
Owen Dando: University of Edinburgh
Sophie R. Thomson: University of Edinburgh
Jennifer C. Darnell: University of Edinburgh
Peter C. Kind: University of Edinburgh
Ka Wan Li: Vrije Universiteit Amsterdam
Emily K. Osterweil: University of Edinburgh

Nature Communications, 2022, vol. 13, issue 1, 1-18

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-30979-0

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