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Dysregulated mi RNA biogenesis downstream of cellular stress and ALS ‐causing mutations: a new mechanism for ALS
Author(s) -
Emde Anna,
Eitan Chen,
Liou LeeLoung,
Libby Ryan T,
Rivkin Natali,
Magen Iddo,
Reichenstein Irit,
Oppenheim Hagar,
Eilam Raya,
Silvestroni Aurelio,
Alajajian Betty,
BenDov Iddo Z,
Aebischer Julianne,
Savidor Alon,
Levin Yishai,
Sons Robert,
Hammond Scott M,
Ravits John M,
Möller Thomas,
Hornstein Eran
Publication year - 2015
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.201490493
Subject(s) - biology , rna , mechanism (biology) , microbiology and biotechnology , biogenesis , gene , genetics , philosophy , epistemology
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 mi RNA levels is a common molecular denominator for multiple forms of human ALS . We further demonstrate that pathogenic ALS ‐causing mutations are sufficient to inhibit mi RNA 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 micro RNA biogenesis under stress, involving stress granule formation and re‐organization of DICER and AGO 2 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 mi RNA biogenesis downstream of the stress response ties seemingly disparate pathways in neurodegeneration and further suggests that DICER and mi RNA s affect neuronal integrity and are possible therapeutic targets.