Dysregulated miRNA biogenesis downstream of cellular stress and ALS-causing mutations: a new mechanism for ALS.
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.
Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.
Anna
A
Emde
Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.
Chen
C
Eitan
Department of Neurology, School of Medicine, University of Washington, Seattle, WA, USA.
Lee-Loung
LL
Liou
Translational Research Program, Benaroya Research Institute at Virginia Mason, Seattle, WA, USA.
Ryan T
RT
Libby
Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.
Natali
N
Rivkin
Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.
Iddo
I
Magen
Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.
Irit
I
Reichenstein
Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.
Hagar
H
Oppenheim
Veterinary Resources, Weizmann Institute of Science, Rehovot, Israel.
Raya
R
Eilam
Department of Neurology, School of Medicine, University of Washington, Seattle, WA, USA.
Aurelio
A
Silvestroni
Department of Neurology, School of Medicine, University of Washington, Seattle, WA, USA.
Betty
B
Alajajian
Nephrology Department, Hadassah - Hebrew University Medical Center, Jerusalem, Israel.
Iddo Z
IZ
Ben-Dov
Brain Mind Institute, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
Julianne
J
Aebischer
de Botton Institute for Protein Profiling, The Nancy and Stephen Grand Israel National Center for Personalized Medicine, Weizmann Institute of Science, Rehovot, Israel.
Alon
A
Savidor
de Botton Institute for Protein Profiling, The Nancy and Stephen Grand Israel National Center for Personalized Medicine, Weizmann Institute of Science, Rehovot, Israel.
Yishai
Y
Levin
Department of Cell Biology and Physiology, School of Medicine, University of North Carolina, Chapel Hill, NC, USA.
Robert
R
Sons
Department of Cell Biology and Physiology, School of Medicine, University of North Carolina, Chapel Hill, NC, USA.
Scott M
SM
Hammond
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.
John M
JM
Ravits
Department of Neurology, School of Medicine, University of Washington, Seattle, WA, USA.
Thomas
T
Möller
Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel jravits@ucsd.edu eran.hornstein@weizmann.ac.il.
Eran
E
Hornstein
D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D000818:Animals; D001483:Base Sequence; D003594:Cytoplasmic Granules / Q000378:metabolism; D053487:DEAD-box RNA Helicases / Q000378:metabolism; D015536:Down-Regulation; D004353:Drug Evaluation, Preclinical; D015365:Enoxacin / Q000494:pharmacology; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000096:biosynthesis* / Q000235:genetics; D009046:Motor Neurons / Q000378:metabolism; D034622:RNA Interference; D012323:RNA Processing, Post-Transcriptional; D043244:Ribonuclease III / Q000378:metabolism; D013312:Stress, Physiological; D013482:Superoxide Dismutase / Q000235:genetics; D000072105:Superoxide Dismutase-1
D035683:MicroRNAs; C000606290:SOD1 protein, human; D015365:Enoxacin; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; C408087:DICER1 protein, human; D043244:Ribonuclease III; D053487:DEAD-box RNA Helicases
ALS; DICER; microRNA; neurodegeneration; stress