ABSTRACT
Mutations in the Fused in Sarcoma (FUS) gene cause the familial and progressive form of amyotrophic lateral sclerosis (ALS). FUS is a nuclear RNA-binding protein involved in RNA processing and the biogenesis of a specific set of microRNAs. Here we report that Drosha and two previously uncharacterized Drosha-dependent miRNAs are strong modulators of FUS expression and prevent the cytoplasmic segregation of insoluble mutant FUS in vivo. We demonstrate that depletion of Drosha mitigates FUS-mediated degeneration, survival and motor defects in Drosophila. Mutant FUS strongly interacts with Drosha and causes its cytoplasmic mis-localization into the insoluble FUS inclusions. Reduction in Drosha levels increases the solubility of mutant FUS. Interestingly, we found two Drosha dependent microRNAs, miR-378i and miR-6832-5p, which differentially regulate the expression, solubility and cytoplasmic aggregation of mutant FUS in iPSC neurons and mammalian cells. More importantly, we report different modes of action of these miRNAs against mutant FUS. Whereas miR-378i may regulate mutant FUS inclusions by preventing G3BP-mediated stress granule formation, miR-6832-5p may affect FUS expression via other proteins or pathways. Overall, our research reveals a possible association between ALS-linked FUS mutations and the Drosha-dependent miRNA regulatory circuit, as well as a useful perspective on potential ALS treatment via microRNAs.
Subject(s)
Drosophila Proteins , Heterogeneous-Nuclear Ribonucleoprotein Group F-H , MicroRNAs , Ribonuclease III , Animals , Amyotrophic Lateral Sclerosis/metabolism , Drosophila/genetics , Drosophila/metabolism , MicroRNAs/genetics , MicroRNAs/metabolism , Mutation , Neurons/metabolism , RNA-Binding Proteins/genetics , RNA-Binding Proteins/metabolism , Neurodegenerative Diseases/metabolism , Heterogeneous-Nuclear Ribonucleoprotein Group F-H/metabolism , Humans , Ribonuclease III/metabolism , Drosophila Proteins/metabolismABSTRACT
OBJECTIVE: To assess the effect of recorded maternal voice on child's cooperation during cardiac catheterization. DESIGN: Randomized placebo controlled trial. SETTING: Cardiac catheterization laboratory at a tertiary care hospital. PARTICIPANTS: 90 children with congenital heart disease scheduled for cardiac catheterization between July 2014 and Dec 2014 randomized to maternal voice group and control group. INTERVENTION: During cardiac catheterization, children in maternal voice group listened to a 3-min audio-recording of their mother's voice, played in loop, using head-phones. Children in the other group wore headphones without auditory stimuli. MAIN OUTCOME MEASURES: Child's cooperation during cardiac catheterization as assessed by Child Emotional Manifestation Scale. RESULTS: Children in the maternal voice group showed lower mean (SD) distress scores [13.2 (4.6) vs. 16 (5.6), P=0.01]. The requirement of sedative agents during the procedure was not different (P=0.09). CONCLUSION: Allowing children to listen to recorded voice of their mother is an effective strategy to improve cooperation during cardiac catheterization.
