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Excess ribosomal protein production unbalances translation in a model of Fragile X Syndrome

Author

Listed:
  • Sang S. Seo

    (University of Edinburgh
    University of Edinburgh)

  • Susana R. Louros

    (University of Edinburgh
    University of Edinburgh)

  • Natasha Anstey

    (University of Edinburgh
    University of Edinburgh)

  • Miguel A. Gonzalez-Lozano

    (Vrije Universiteit Amsterdam)

  • Callista B. Harper

    (University of Edinburgh
    University of Edinburgh)

  • Nicholas C. Verity

    (University of Edinburgh
    University of Edinburgh)

  • Owen Dando

    (University of Edinburgh
    University of Edinburgh)

  • Sophie R. Thomson

    (University of Edinburgh
    University of Edinburgh)

  • Jennifer C. Darnell

    (University of Edinburgh
    University of Edinburgh)

  • Peter C. Kind

    (University of Edinburgh
    University of Edinburgh)

  • Ka Wan Li

    (Vrije Universiteit Amsterdam)

  • Emily K. Osterweil

    (University of Edinburgh
    University of Edinburgh)

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.

Suggested Citation

  • Sang S. Seo & Susana R. Louros & Natasha Anstey & Miguel A. Gonzalez-Lozano & Callista B. Harper & Nicholas C. Verity & Owen Dando & Sophie R. Thomson & Jennifer C. Darnell & Peter C. Kind & Ka Wan Li, 2022. "Excess ribosomal protein production unbalances translation in a model of Fragile X Syndrome," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-30979-0
    DOI: 10.1038/s41467-022-30979-0
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    References listed on IDEAS

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    1. Ian F. King & Chandri N. Yandava & Angela M. Mabb & Jack S. Hsiao & Hsien-Sung Huang & Brandon L. Pearson & J. Mauro Calabrese & Joshua Starmer & Joel S. Parker & Terry Magnuson & Stormy J. Chamberlai, 2013. "Topoisomerases facilitate transcription of long genes linked to autism," Nature, Nature, vol. 501(7465), pages 58-62, September.
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    3. Heather Bowling & Aditi Bhattacharya & Guoan Zhang & Danyal Alam & Joseph Z. Lebowitz & Nathaniel Bohm-Levine & Derek Lin & Priyangvada Singha & Maggie Mamcarz & Rosemary Puckett & Lili Zhou & Sameer , 2019. "Altered steady state and activity-dependent de novo protein expression in fragile X syndrome," Nature Communications, Nature, vol. 10(1), pages 1-13, December.
    4. Claudia M. Fusco & Kristina Desch & Aline R. Dörrbaum & Mantian Wang & Anja Staab & Ivy C. W. Chan & Eleanor Vail & Veronica Villeri & Julian D. Langer & Erin M. Schuman, 2021. "Neuronal ribosomes exhibit dynamic and context-dependent exchange of ribosomal proteins," Nature Communications, Nature, vol. 12(1), pages 1-14, December.
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