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

Dysregulated protein synthesis is key contributor to Fragile X syndrome. Here the authors identify a relationship between ribosome expression and the translation of long mRNAs that contributes to synaptic weakening in a model of Fragile X syndrome.

Details

Title
Excess ribosomal protein production unbalances translation in a model of Fragile X Syndrome
Author
Seo, Sang S. 1 ; Louros, Susana R. 1 ; Anstey, Natasha 1 ; Gonzalez-Lozano, Miguel A. 2   VIAFID ORCID Logo  ; Harper, Callista B. 1 ; Verity, Nicholas C. 1 ; Dando, Owen 1   VIAFID ORCID Logo  ; Thomson, Sophie R. 1 ; Darnell, Jennifer C. 1 ; Kind, Peter C. 1 ; Li, Ka Wan 2   VIAFID ORCID Logo  ; Osterweil, Emily K. 1   VIAFID ORCID Logo 

1  University of Edinburgh, Centre for Discovery Brain Sciences, Edinburgh, UK (GRID:grid.4305.2) (ISNI:0000 0004 1936 7988); University of Edinburgh, Simons Initiative for the Developing Brain, Edinburgh, UK (GRID:grid.4305.2) (ISNI:0000 0004 1936 7988) 
2  Vrije Universiteit Amsterdam, Department of Molecular and Cellular Neurobiology, Center for Neurogenomics and Cognitive Research, Amsterdam, Netherlands (GRID:grid.12380.38) (ISNI:0000 0004 1754 9227) 
Publication year
2022
Publication date
2022
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41467-022-30979-0
ProQuest document ID
2675088162
Copyright
© The Author(s) 2022. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.