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An ALS-associated mutation in the FUS 3′-UTR disrupts a microRNA–FUS regulatory circuitry

Author

Listed:
  • Stefano Dini Modigliani

    (Center for Life Nano Science@Sapienza, Istituto Italiano di Tecnologia, Viale Regina Elena 291)

  • Mariangela Morlando

    (Sapienza University of Rome, P.le A. Moro 5, 00185 Rome, Italy)

  • Lorenzo Errichelli

    (Center for Life Nano Science@Sapienza, Istituto Italiano di Tecnologia, Viale Regina Elena 291
    Sapienza University of Rome, P.le A. Moro 5, 00185 Rome, Italy)

  • Mario Sabatelli

    (Institute Pasteur Fondazione Cenci-Bolognetti, Sapienza University of Rome, P.le A. Moro 5, 00185 Rome, Italy)

  • Irene Bozzoni

    (Center for Life Nano Science@Sapienza, Istituto Italiano di Tecnologia, Viale Regina Elena 291
    Sapienza University of Rome, P.le A. Moro 5, 00185 Rome, Italy
    Neuroscience and Orthopedics, Institute of Neurology, Catholic University, L.go A. Gemelli 8)

Abstract

While the physiologic functions of the RNA-binding protein FUS still await thorough characterization, the pathonegetic role of FUS mutations in amyotrophic lateral sclerosis (ALS) is clearly established. Here we find that a human FUS mutation that leads to increased protein expression, and was identified in two ALS patients with severe outcome, maps to the seed sequence recognized by miR-141 and miR-200a in the 3′-UTR of FUS. We demonstrate that FUS and these microRNAs are linked by a feed-forward regulatory loop where FUS upregulates miR-141/200a, which in turn impact FUS protein synthesis. We also show that Zeb1, a target of miR-141/200a and transcriptional repressor of these two microRNAs, is part of the circuitry and reinforces it. Our results reveal a possible correlation between deregulation of this regulatory circuit and ALS pathogenesis, and open interesting perspectives in the treatment of these mutations through ad hoc-modified microRNAs.

Suggested Citation

  • Stefano Dini Modigliani & Mariangela Morlando & Lorenzo Errichelli & Mario Sabatelli & Irene Bozzoni, 2014. "An ALS-associated mutation in the FUS 3′-UTR disrupts a microRNA–FUS regulatory circuitry," Nature Communications, Nature, vol. 5(1), pages 1-7, September.
    • Handle: RePEc:nat:natcom:v:5:y:2014:i:1:d:10.1038_ncomms5335
    DOI: 10.1038/ncomms5335
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