Journal article
Dysregulated miRNA biogenesis downstream of cellular stress and ALS-causing mutations: a new mechanism for ALS.
The EMBO Journal, Vol.34(21), pp.2633-51
Nov/2015
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.
Details
- Title
- Dysregulated miRNA biogenesis downstream of cellular stress and ALS-causing mutations; a new mechanism for ALS.
- Creators
- Anna Emde (null)Chen Eitan (null) - 972WIS_INST___111Lee-Loung Liou (null)Ryan T Libby (null)Natali Rivkin (null)Iddo Magen (null) - 972WIS_INST___111Irit Reichenstein (null) - 972WIS_INST___111Hagar Oppenheim (null) - The Weizmann Institute of ScienceRaya Eilam (null)Aurelio Silvestroni (null)Betty Alajajian (null)Iddo Z Ben-Dov (null)Julianne Aebischer (null)Alon Savidor (null) - 972WIS_INST___972Yishai Levin (null) - The Weizmann Institute of ScienceRobert Sons (null)Scott M Hammond (null)John M Ravits (null)Thomas Moller (null)Eran Hornstein (null) - 972WIS_INST___111
- Resource Type
- Journal article
- Publication Details
- The EMBO Journal, Vol.34(21), pp.2633-51; Nov/2015
- Language
- English
- DOI
- https://doi.org/10.15252/embj.201490493
- Grant note
- 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 We thank Ranjan Batra (University of California, SD) for sharing bioinformatics analysis from ongoing studies; Markus Landthaler (Max Delbruck Center for Molecular Medicine), Daryl Bosco (University of Massachusetts, Boston), Zissimos Mourelatos (University of Pennsylvania), Yoram Groner, Menachem Rubinstein, Ari Elson (Weizmann Institute of Science), David Ron (CIMR, University of Cambridge), William Hahn (Dana Farber Cancer Institute, HMS) and David Sabatini (Whitehead Institute, MIT) for vectors and reagents; Pat Janssen and Fred Farin (UW Functional Genomics and Bioinformatics Core Laboratory) for technical assistance and troubleshooting; and Tal Yardeni (Weizmann Institute of Science) for whole spinal cord RNA. We further thank Daniel Dar (Weizmann Institute of Science) for RNA analysis, Chaim Kahana (Weizmann Institute of Science), Orna Elroy-Stein (Tel Aviv University), Markus Weber (Kantonsspital St. Gallen), Witold Filipowicz (FMI, Basel), Bernard Schneider (EPFL, Lausanne), Mark A. Behlke (Integrated DNA Technologies, Inc.) and Peter Andersen (Umea University) for discussions and advice and Danielle Aronowitz for English editing. This work was supported by grants to E.H. from the Israel Science Foundation, the ISF Legacy-heritage Program, The 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 and the ALS-Therapy Alliance. Additional funding was from 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,_ALMAME_DELIMITER_
- Record Identifier
- 993262846203596
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