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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...

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Detalles Bibliográficos
Autores principales: Seo, Sang S., Louros, Susana R., Anstey, Natasha, Gonzalez-Lozano, Miguel A., Harper, Callista B., Verity, Nicholas C., Dando, Owen, Thomson, Sophie R., Darnell, Jennifer C., Kind, Peter C., Li, Ka Wan, Osterweil, Emily K.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2022
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
Descripción
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.