IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v9y2018i1d10.1038_s41467-018-04110-1.html
   My bibliography  Save this article

Targeting RNA structure in SMN2 reverses spinal muscular atrophy molecular phenotypes

Author

Listed:
  • Amparo Garcia-Lopez

    (University of Lausanne and University of Geneva)

  • Francesca Tessaro

    (University of Lausanne and University of Geneva)

  • Hendrik R. A. Jonker

    (Johann Wolfgang Goethe-University Frankfurt)

  • Anna Wacker

    (Johann Wolfgang Goethe-University Frankfurt)

  • Christian Richter

    (Johann Wolfgang Goethe-University Frankfurt)

  • Arnaud Comte

    (University Claude Bernard Lyon 1)

  • Nikolaos Berntenis

    (F. Hoffmann-La Roche)

  • Roland Schmucki

    (F. Hoffmann-La Roche)

  • Klas Hatje

    (F. Hoffmann-La Roche)

  • Olivier Petermann

    (University of Lausanne and University of Geneva)

  • Gianpaolo Chiriano

    (University of Lausanne and University of Geneva)

  • Remo Perozzo

    (University of Lausanne and University of Geneva)

  • Daniel Sciarra

    (University of Lausanne and University of Geneva)

  • Piotr Konieczny

    (Incliva Health Research Institute
    University of Valencia)

  • Ignacio Faustino

    (Joint BSC-IRB Research Program in Computational Biology)

  • Guy Fournet

    (University Claude Bernard Lyon 1)

  • Modesto Orozco

    (Joint BSC-IRB Research Program in Computational Biology)

  • Ruben Artero

    (Incliva Health Research Institute
    University of Valencia)

  • Friedrich Metzger

    (F. Hoffmann-La Roche)

  • Martin Ebeling

    (F. Hoffmann-La Roche)

  • Peter Goekjian

    (University Claude Bernard Lyon 1)

  • Benoît Joseph

    (University Claude Bernard Lyon 1)

  • Harald Schwalbe

    (Johann Wolfgang Goethe-University Frankfurt)

  • Leonardo Scapozza

    (University of Lausanne and University of Geneva)

Abstract

Modification of SMN2 exon 7 (E7) splicing is a validated therapeutic strategy against spinal muscular atrophy (SMA). However, a target-based approach to identify small-molecule E7 splicing modifiers has not been attempted, which could reveal novel therapies with improved mechanistic insight. Here, we chose as a target the stem-loop RNA structure TSL2, which overlaps with the 5′ splicing site of E7. A small-molecule TSL2-binding compound, homocarbonyltopsentin (PK4C9), was identified that increases E7 splicing to therapeutic levels and rescues downstream molecular alterations in SMA cells. High-resolution NMR combined with molecular modelling revealed that PK4C9 binds to pentaloop conformations of TSL2 and promotes a shift to triloop conformations that display enhanced E7 splicing. Collectively, our study validates TSL2 as a target for small-molecule drug discovery in SMA, identifies a novel mechanism of action for an E7 splicing modifier, and sets a precedent for other splicing-mediated diseases where RNA structure could be similarly targeted.

Suggested Citation

  • Amparo Garcia-Lopez & Francesca Tessaro & Hendrik R. A. Jonker & Anna Wacker & Christian Richter & Arnaud Comte & Nikolaos Berntenis & Roland Schmucki & Klas Hatje & Olivier Petermann & Gianpaolo Chir, 2018. "Targeting RNA structure in SMN2 reverses spinal muscular atrophy molecular phenotypes," Nature Communications, Nature, vol. 9(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-04110-1
    DOI: 10.1038/s41467-018-04110-1
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-018-04110-1
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-018-04110-1?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
    ---><---

    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:9:y:2018:i:1:d:10.1038_s41467-018-04110-1. 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.

    We have no bibliographic references for this item. You can help adding them by using 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.