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Nat Commun. 2014 Jul 9;5:4335. doi: 10.1038/ncomms5335.

An ALS-associated mutation in the FUS 3'-UTR disrupts a microRNA-FUS regulatory circuitry.

Author information

1
1] Center for Life Nano Science@Sapienza, Istituto Italiano di Tecnologia, Viale Regina Elena 291, 00161 Rome, Italy [2].
2
1] Department of Biology and Biotechnology Charles Darwin and IBPM, Sapienza University of Rome, P.le A. Moro 5, 00185 Rome, Italy [2].
3
1] Center for Life Nano Science@Sapienza, Istituto Italiano di Tecnologia, Viale Regina Elena 291, 00161 Rome, Italy [2] Department of Biology and Biotechnology Charles Darwin and IBPM, Sapienza University of Rome, P.le A. Moro 5, 00185 Rome, Italy.
4
Institute Pasteur Fondazione Cenci-Bolognetti, Sapienza University of Rome, P.le A. Moro 5, 00185 Rome, Italy.
5
1] Center for Life Nano Science@Sapienza, Istituto Italiano di Tecnologia, Viale Regina Elena 291, 00161 Rome, Italy [2] Department of Biology and Biotechnology Charles Darwin and IBPM, Sapienza University of Rome, P.le A. Moro 5, 00185 Rome, Italy [3] Department of Geriatrics, Neuroscience and Orthopedics, Institute of Neurology, Catholic University, L.go A. Gemelli 8, 00168 Rome, Italy.

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.

PMID:
25004804
DOI:
10.1038/ncomms5335
[Indexed for MEDLINE]

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