Excess ribosomal protein production unbalances translation in a model of Fragile X Syndrome.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 35688821.
- Also identified by DOI 10.1038/s41467-022-30979-0 and PMC identifier 9187743.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
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 mGlu<sub>1/5</sub> activation. Here, we use a combination of CA1 pyramidal neuron-specific TRAP-seq and proteomics to identify the overtranslating mRNAs supporting exaggerated mGlu<sub>1/5</sub> -induced long-term synaptic depression (mGluR-LTD) in the FX mouse model (Fmr1<sup>-/y</sup>). Our results identify a significant increase in the translation of ribosomal proteins (RPs) upon mGlu<sub>1/5</sub> stimulation that coincides with a reduced translation of long mRNAs encoding synaptic proteins. These changes are mimicked and occluded in Fmr1<sup>-/y</sup> 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.
Medical subject headings
- Fragile X Syndrome
- Receptors, Metabotropic Glutamate