Excess ribosomal protein production unbalances translation in Fragile X Syndrome

Seo, S. S.; Louros, S. R.; Anstey, N.; Gonzalez-Lazano, M. A.; Thomson, S. R.; Harper, C.; Verity, N.; Darnell, J. C.; Li, K. W.; Kind, P. C.; Osterweil, E. K.

doi:10.1101/2022.04.07.487442

bioRxiv · 10.1101/2022.04.07.487442

Excess ribosomal protein production unbalances translation in Fragile X Syndrome

Seo, S. S.·Louros, S. R.·Anstey, N.·Gonzalez-Lazano, M. A.·Thomson, S. R.·Harper, C.·Verity, N.·Darnell, J. C.·Li, K. W.·Kind, P. C.·Osterweil, E. K.

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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). Surprisingly, our results identify a robust 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.

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Seo, S. S., Louros, S. R., Anstey, N., Gonzalez-Lazano, M. A., Thomson, S. R., Harper, C., Verity, N., Darnell, J. C., Li, K. W., Kind, P. C., Osterweil, E. K.. 2022-04-08. Excess ribosomal protein production unbalances translation in Fragile X Syndrome. https://doi.org/10.1101/2022.04.07.487442

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