The cooperative binding of TDP-43 to GU-rich RNA repeats antagonizes TDP-43 aggregation

  1. Juan Carlos Rengifo-Gonzalez
  2. Krystel El Hage
  3. Marie-Jeanne Clément
  4. Emilie Steiner
  5. Vandana Joshi
  6. Pierrick Craveur
  7. Dominique Durand
  8. David Pastré  Is a corresponding author
  9. Ahmed Bouhss  Is a corresponding author
  1. Université Paris-Saclay, INSERM U1204, Univ Evry, France
  2. SYNSIGHT, France
  3. Université Paris-Saclay, CEA, CNRS, France

Abstract

TDP-43 is a nuclear RNA-binding protein that forms neuronal cytoplasmic inclusions in two major neurodegenerative diseases, ALS and FTLD. While the self-assembly of TDP-43 by its structured N-terminal and intrinsically disordered C-terminal domains has been widely studied, the mechanism by which mRNA preserves TDP-43 solubility in the nucleus has not been addressed. Here, we demonstrate that tandem RNA Recognition Motifs of TDP-43 bind to long GU-repeats in a cooperative manner through intermolecular interactions. Moreover, using mutants whose cooperativity is impaired, we found that the cooperative binding of TDP-43 to mRNA may be critical to maintain the solubility of TDP-43 in the nucleus and the miscibility of TDP-43 in cytoplasmic stress granules. We anticipate that the knowledge of a higher order assembly of TDP-43 on mRNA may clarify its role in intron processing and provide a means of interfering with the cytoplasmic aggregation of TDP-43.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files.

The following previously published data sets were used

Article and author information

Author details

  1. Juan Carlos Rengifo-Gonzalez

    SABNP, Université Paris-Saclay, INSERM U1204, Univ Evry, Evry, France
    Competing interests
    The authors declare that no competing interests exist.
  2. Krystel El Hage

    Department of Chemistry, Université Paris-Saclay, INSERM U1204, Univ Evry, Evry, France
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4837-3888
  3. Marie-Jeanne Clément

    SABNP, Université Paris-Saclay, INSERM U1204, Univ Evry, Evry, France
    Competing interests
    The authors declare that no competing interests exist.
  4. Emilie Steiner

    laboratoire structure activité des biomolécules normales et pathologiques, Université Paris-Saclay, INSERM U1204, Univ Evry, Evry, France
    Competing interests
    The authors declare that no competing interests exist.
  5. Vandana Joshi

    laboratoire structure activité des biomolécules normales et pathologiques, Université Paris-Saclay, INSERM U1204, Univ Evry, Evry, France
    Competing interests
    The authors declare that no competing interests exist.
  6. Pierrick Craveur

    SYNSIGHT, Evry, France
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9274-4944
  7. Dominique Durand

    Institute for Integrative Biology of the Cell (I2BC), Université Paris-Saclay, CEA, CNRS, Gif-sur-Yvette, France
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9414-5857
  8. David Pastré

    SABNP, Université Paris-Saclay, INSERM U1204, Univ Evry, Evry, France
    For correspondence
    david.pastre@univ-evry.fr
    Competing interests
    The authors declare that no competing interests exist.
  9. Ahmed Bouhss

    Structure-Activité des Biomolécules Normales et Pathologiques (SABNP), Université Paris-Saclay, INSERM U1204, Univ Evry, Evry, France
    For correspondence
    ahmed.bouhss@univ-evry.fr
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6492-1429

Funding

Genopole (SATURNE 2018-SABNP)

  • Ahmed Bouhss

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Rohit V Pappu, Washington University in St Louis, United States

Version history

  1. Received: February 16, 2021
  2. Accepted: September 3, 2021
  3. Accepted Manuscript published: September 7, 2021 (version 1)
  4. Accepted Manuscript updated: September 10, 2021 (version 2)
  5. Version of Record published: October 18, 2021 (version 3)

Copyright

© 2021, Rengifo-Gonzalez et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Juan Carlos Rengifo-Gonzalez
  2. Krystel El Hage
  3. Marie-Jeanne Clément
  4. Emilie Steiner
  5. Vandana Joshi
  6. Pierrick Craveur
  7. Dominique Durand
  8. David Pastré
  9. Ahmed Bouhss
(2021)
The cooperative binding of TDP-43 to GU-rich RNA repeats antagonizes TDP-43 aggregation
eLife 10:e67605.
https://doi.org/10.7554/eLife.67605

Share this article

https://doi.org/10.7554/eLife.67605

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