IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v13y2022i1d10.1038_s41467-022-30979-0.html
   My bibliography  Save this article

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
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-022-30979-0
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-022-30979-0?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Shahar Shohat & Sagiv Shifman, 2014. "Bias towards large genes in autism," Nature, Nature, vol. 512(7512), pages 1-2, August.
    2. 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.
    3. 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.
    4. 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.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Hanna Vihma & Kelin Li & Anna Welton-Arndt & Audrey L. Smith & Kiran R. Bettadapur & Rachel B. Gilmore & Eric Gao & Justin L. Cotney & Hsueh-Cheng Huang & Jon L. Collins & Stormy J. Chamberlain & Hyeo, 2024. "Ube3a unsilencer for the potential treatment of Angelman syndrome," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    2. Naomi R. Genuth & Zhen Shi & Koshi Kunimoto & Victoria Hung & Adele F. Xu & Craig H. Kerr & Gerald C. Tiu & Juan A. Oses-Prieto & Rachel E. A. Salomon-Shulman & Jeffrey D. Axelrod & Alma L. Burlingame, 2022. "A stem cell roadmap of ribosome heterogeneity reveals a function for RPL10A in mesoderm production," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    3. Abdolhossein Zare & Saeede Salehi & Jakob Bader & Cornelius Schneider & Utz Fischer & Alexander Veh & Panagiota Arampatzi & Matthias Mann & Michael Briese & Michael Sendtner, 2024. "hnRNP R promotes O-GlcNAcylation of eIF4G and facilitates axonal protein synthesis," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
    4. Chen Sun & Kunal Kathuria & Sarah B. Emery & ByungJun Kim & Ian E. Burbulis & Joo Heon Shin & Daniel R. Weinberger & John V. Moran & Jeffrey M. Kidd & Ryan E. Mills & Michael J. McConnell, 2024. "Mapping recurrent mosaic copy number variation in human neurons," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    5. Saeede Salehi & Abdolhossein Zare & Gianluca Prezza & Jakob Bader & Cornelius Schneider & Utz Fischer & Felix Meissner & Matthias Mann & Michael Briese & Michael Sendtner, 2023. "Cytosolic Ptbp2 modulates axon growth in motoneurons through axonal localization and translation of Hnrnpr," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    6. Mei Sheng Lau & Zhenhua Hu & Xiaodan Zhao & Yaw Sing Tan & Jinyue Liu & Hua Huang & Clarisse Jingyi Yeo & Hwei Fen Leong & Oleg V. Grinchuk & Justin Kaixuan Chan & Jie Yan & Wee-Wei Tee, 2023. "Transcriptional repression by a secondary DNA binding surface of DNA topoisomerase I safeguards against hypertranscription," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    7. Junho Kim & August Yue Huang & Shelby L. Johnson & Jenny Lai & Laura Isacco & Ailsa M. Jeffries & Michael B. Miller & Michael A. Lodato & Christopher A. Walsh & Eunjung Alice Lee, 2022. "Prevalence and mechanisms of somatic deletions in single human neurons during normal aging and in DNA repair disorders," Nature Communications, Nature, vol. 13(1), pages 1-13, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-30979-0. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.