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EMBO J. 2015 Nov 3;34(21):2633-51. doi: 10.15252/embj.201490493. Epub 2015 Sep 1.

Dysregulated miRNA biogenesis downstream of cellular stress and ALS-causing mutations: a new mechanism for ALS.

Author information

1
Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.
2
Department of Neurology, School of Medicine, University of Washington, Seattle, WA, USA.
3
Translational Research Program, Benaroya Research Institute at Virginia Mason, Seattle, WA, USA.
4
Veterinary Resources, Weizmann Institute of Science, Rehovot, Israel.
5
Nephrology Department, Hadassah - Hebrew University Medical Center, Jerusalem, Israel.
6
Brain Mind Institute, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
7
de Botton Institute for Protein Profiling, The Nancy and Stephen Grand Israel National Center for Personalized Medicine, Weizmann Institute of Science, Rehovot, Israel.
8
Department of Cell Biology and Physiology, School of Medicine, University of North Carolina, Chapel Hill, NC, USA.
9
Translational Research Program, Benaroya Research Institute at Virginia Mason, Seattle, WA, USA Department of Neurosciences, UC San Diego, La Jolla, CA, USA jravits@ucsd.edu eran.hornstein@weizmann.ac.il.
10
Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel jravits@ucsd.edu eran.hornstein@weizmann.ac.il.

Abstract

Interest in RNA dysfunction in amyotrophic lateral sclerosis (ALS) recently aroused upon discovering causative mutations in RNA-binding protein genes. Here, we show that extensive down-regulation of miRNA levels is a common molecular denominator for multiple forms of human ALS. We further demonstrate that pathogenic ALS-causing mutations are sufficient to inhibit miRNA biogenesis at the Dicing step. Abnormalities of the stress response are involved in the pathogenesis of neurodegeneration, including ALS. Accordingly, we describe a novel mechanism for modulating microRNA biogenesis under stress, involving stress granule formation and re-organization of DICER and AGO2 protein interactions with their partners. In line with this observation, enhancing DICER activity by a small molecule, enoxacin, is beneficial for neuromuscular function in two independent ALS mouse models. Characterizing miRNA biogenesis downstream of the stress response ties seemingly disparate pathways in neurodegeneration and further suggests that DICER and miRNAs affect neuronal integrity and are possible therapeutic targets.

KEYWORDS:

ALS; DICER; microRNA; neurodegeneration; stress

PMID:
26330466
PMCID:
PMC4641530
DOI:
10.15252/embj.201490493
[Indexed for MEDLINE]
Free PMC Article

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