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

Stefano Dini Modigliani, Mariangela Morlando (), Lorenzo Errichelli, Mario Sabatelli and Irene Bozzoni ()
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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
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

Nature Communications, 2014, vol. 5, issue 1, 1-7

Abstract: 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.

Date: 2014
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DOI: 10.1038/ncomms5335

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