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An ALS-associated mutation in the FUS 3′-UTR disrupts a microRNA–FUS regulatory circuitry
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An ALS-associated mutation in the FUS 3′-UTR disrupts a microRNA–FUS regulatory circuitry
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Journal Article
An ALS-associated mutation in the FUS 3′-UTR disrupts a microRNA–FUS regulatory circuitry
2014
Overview
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.
Abnormal accumulation of the RNA-binding protein FUS and mutations within the
FUS
gene have been found in association with amyotrophic lateral sclerosis (ALS). Here, Dini Modigliani
et al.
uncover a FUS regulatory circuit that implicates the microRNAs miR-141 and miR-200a in a feedback loop disrupted by an ALS-associated mutation.
Publisher
Nature Publishing Group UK,Nature Publishing Group
Subject
/ 38/1
/ 38/109
/ 38/15
/ 38/71
/ 38/77
/ 38/89
/ 38/90
/ 692/420
/ 82/29
/ 82/80
/ Amyotrophic Lateral Sclerosis - genetics
/ Amyotrophic Lateral Sclerosis - metabolism
/ Homeodomain Proteins - genetics
/ Homeodomain Proteins - metabolism
/ Humanities and Social Sciences
/ Humans
/ Mutation
/ RNA-Binding Protein FUS - genetics
/ RNA-Binding Protein FUS - metabolism
/ Science
/ Transcription Factors - genetics
