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

Seo SS*, Louros SR*, Anstey N, Gonzales-Lozano MA, Harper CB, Verity NC, Dando O, Thomson SR, Darnell JC, Kind PC, Li KW, and Osterweil EK. Excess ribogenesis unbalances translation in a model of Fragile X Syndrome. Nat Commun. 2022 Jun 10;13(1):3236. doi: 10.1038/s41467-022-30979-0. PubMed PMID: 35688821.

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 resu¬lts suggest that pathological changes in FX result from a length-dependent alteration in the translating population that is supported by excessive RP translation.