Dysregulated mi RNA biogenesis downstream of cellular stress and ALS ‐causing mutations: a new mechanism for ALS

• DOI: 10.15252/embj.201490493
• Publication Date: 2015-09-02T01:14:23Z
• Authors: Anna Emde; Chen Eitan; Lee‐Loung Liou; Ryan T Libby; Natali Rivkin; Iddo Magen; Irit Reichenstein; Hagar Oppenheim; Raya Eilam; Aurelio Silvestroni; Betty Alajajian; Iddo Z Ben‐Dov; Julianne Aebischer; Alon Savidor; Yishai Levin; Robert Sons; Scott M Hammond; John M Ravits; Thomas Möller; Eran Hornstein
• Keywords: Enoxacin; Male; Ribonuclease III; Biomedical and clinical sciences; Drug Evaluation, Preclinical; Post-Transcriptional; Neurodegenerative; Inbred C57BL; Medical and Health Sciences; Transgenic; DEAD-box RNA Helicases; Mice; stress; Superoxide Dismutase-1; 2.1 Biological and endogenous factors; Aetiology; RNA Processing, Post-Transcriptional; Motor Neurons; microRNA; neurodegeneration; Biological Sciences; Preclinical; Biological sciences; Neurological; Female; RNA Interference; Biotechnology; RNA Processing; Physiological; Down-Regulation; Mice, Transgenic; Stress; Cytoplasmic Granules; Rare Diseases; Stress, Physiological; Information and Computing Sciences; Genetics; Animals; Humans; Base Sequence; Superoxide Dismutase; Amyotrophic Lateral Sclerosis; Neurosciences; DICER; Brain Disorders; Mice, Inbred C57BL; MicroRNAs; HEK293 Cells; Drug Evaluation; Biochemistry and Cell Biology; ALS; Developmental Biology

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.