Journal
EMBO JOURNAL
Volume 34, Issue 21, Pages 2633-2651Publisher
WILEY
DOI: 10.15252/embj.201490493
Keywords
microRNA; ALS; stress; neurodegeneration; DICER
Categories
Funding
- Israel Science Foundation
- ISF Legacy-heritage Program
- Bruno and Ilse Frick Foundation for Research on ALS
- Yeda-Sela
- Yeda-CEO fund
- Minna-James-Heineman Stiftung through Minerva
- ERC Consolidator Program
- Israel Ministry of Industry, Trade and Labor Kamin Program
- Nella and Leon Benoziyo Center for Neurological Diseases
- Y. Leon Benoziyo Institute for Molecular Medicine
- ALS-Therapy Alliance
- Kekst Family Institute for Medical Genetics
- David and Fela Shapell Family Center for Genetic Disorders Research
- Crown Human Genome Center
- Nathan
- Shirley
- Philip and Charlene Vener New Scientist Fund
- Julius and Ray Charlestein Foundation
- Fraida Foundation
- Wolfson Family Charitable Trust
- Adelis Foundation
- MERCK UK
- Maria Halphen
- Estate of Fannie Sherr
- Estate of Lola Asseof
- Estate of Lilly Fulop
- National Network of Excellence in Neuroscience (NNE)
- Teva and miCure Therapeutics
- ALS Association [1765]
- NIH T32 fellowship [NS051171]
- Microsoft Research
- family of T. Evans Wyckoff
- friend of Greg Brooks
- friend of Lois Caprile
- Deutsche Forschungsgemeinschaft
- Dr. Sidney Brenner and friends
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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.
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