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: Stefano Dini Modigliani, Mariangela Morlando, Lorenzo Errichelli, Mario Sabatelli, Irene Bozzoni
• Journal: Nature communications (Nat Commun) Vol. 5 Pg. 4335 (Jul 09 2014) ISSN: 2041-1723 [Electronic] England
• PMID: 25004804 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 3' Untranslated Regions
• Homeodomain Proteins
• MIRN141 microRNA, human
• MIRN200 microRNA, human
• MicroRNAs
• RNA-Binding Protein FUS
• Transcription Factors
• ZEB1 protein, human
• Zinc Finger E-box-Binding Homeobox 1

Topics

• 3' Untranslated Regions
• Amyotrophic Lateral Sclerosis (genetics, metabolism)
• Gene Expression Regulation
• Homeodomain Proteins (genetics, metabolism)
• Humans
• MicroRNAs (genetics, metabolism)
• Mutation
• RNA-Binding Protein FUS (genetics, metabolism)
• Transcription Factors (genetics, metabolism)
• Zinc Finger E-box-Binding Homeobox 1