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Excess ribosomal protein production unbalances translation in a model of Fragile X Syndrome
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(1/5) activation. Here, we use a combination of CA1 pyramidal neuron-specific T...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9187743/ https://www.ncbi.nlm.nih.gov/pubmed/35688821 http://dx.doi.org/10.1038/s41467-022-30979-0 |
Sumario: | 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(1/5) activation. Here, we use a combination of CA1 pyramidal neuron-specific TRAP-seq and proteomics to identify the overtranslating mRNAs supporting exaggerated mGlu(1/5) -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 mGlu(1/5) 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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