title: An ALS-associated mutation in the FUS 3'-UTR disrupts a microRNA-FUS regulatory circuitry.
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.
authors.affiliation: 1] Center for Life Nano Science@Sapienza, Istituto Italiano di Tecnologia, Viale Regina Elena 291, 00161 Rome, Italy [2].
authors.forename: Stefano
authors.initials: S
authors.lastname: Dini Modigliani
authors.affiliation: 1] Department of Biology and Biotechnology Charles Darwin and IBPM, Sapienza University of Rome, P.le A. Moro 5, 00185 Rome, Italy [2].
authors.forename: Mariangela
authors.initials: M
authors.lastname: Morlando
authors.affiliation: 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.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Errichelli
authors.affiliation: Institute Pasteur Fondazione Cenci-Bolognetti, Sapienza University of Rome, P.le A. Moro 5, 00185 Rome, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Sabatelli
authors.affiliation: 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.
authors.forename: Irene
authors.initials: I
authors.lastname: Bozzoni
mesh_terms: D020413:3' Untranslated Regions; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D034702:RNA-Binding Protein FUS / Q000235:genetics* / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D000071799:Zinc Finger E-box-Binding Homeobox 1
chemical_list: D020413:3' Untranslated Regions; D018398:Homeodomain Proteins; C533895:MIRN141 microRNA, human; C533896:MIRN200 microRNA, human; D035683:MicroRNAs; D034702:RNA-Binding Protein FUS; D014157:Transcription Factors; C486307:ZEB1 protein, human; D000071799:Zinc Finger E-box-Binding Homeobox 1