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

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

  • 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