title: The ADAR RNA editing enzyme controls neuronal excitability in Drosophila melanogaster.
abstract: RNA editing by deamination of specific adenosine bases to inosines during pre-mRNA processing generates edited isoforms of proteins. Recoding RNA editing is more widespread in Drosophila than in vertebrates. Editing levels rise strongly at metamorphosis, and Adar(5G1) null mutant flies lack editing events in hundreds of CNS transcripts; mutant flies have reduced viability, severely defective locomotion and age-dependent neurodegeneration. On the other hand, overexpressing an adult dADAR isoform with high enzymatic activity ubiquitously during larval and pupal stages is lethal. Advantage was taken of this to screen for genetic modifiers; Adar overexpression lethality is rescued by reduced dosage of the Rdl (Resistant to dieldrin), gene encoding a subunit of inhibitory GABA receptors. Reduced dosage of the Gad1 gene encoding the GABA synthetase also rescues Adar overexpression lethality. Drosophila Adar(5G1) mutant phenotypes are ameliorated by feeding GABA modulators. We demonstrate that neuronal excitability is linked to dADAR expression levels in individual neurons; Adar-overexpressing larval motor neurons show reduced excitability whereas Adar(5G1) null mutant or targeted Adar knockdown motor neurons exhibit increased excitability. GABA inhibitory signalling is impaired in human epileptic and autistic conditions, and vertebrate ADARs may have a relevant evolutionarily conserved control over neuronal excitability.
authors.affiliation: MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine at the University of Edinburgh, Crewe Road, Edinburgh EH4 2XU, Scotland, UK, Faculty of Life Sciences, University of Manchester, Oxford Road, Manchester M13 9PT, UK and Department of Molecular Biosciences, The Wenner Gren Institute, Stockholm University, Svante Arrhenius väg 20C, 106 91 Stockholm, Sweden.
authors.forename: Xianghua
authors.initials: X
authors.lastname: Li
authors.forename: Ian M
authors.initials: IM
authors.lastname: Overton
authors.forename: Richard A
authors.initials: RA
authors.lastname: Baines
authors.forename: Liam P
authors.initials: LP
authors.lastname: Keegan
authors.forename: Mary A
authors.initials: MA
authors.lastname: O'Connell
mesh_terms: D000200:Action Potentials; D000243:Adenosine Deaminase / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D059006:Chromosomes, Insect; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000201:enzymology* / Q000235:genetics / Q000502:physiology; D005804:Genes, Lethal; D005838:Genotype; D007814:Larva / Q000201:enzymology; D009046:Motor Neurons / Q000201:enzymology* / Q000502:physiology; D010641:Phenotype; D017393:RNA Editing; D011963:Receptors, GABA-A / Q000235:genetics; D015398:Signal Transduction; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D029721:Drosophila Proteins; C082030:Rdl protein, Drosophila; D011963:Receptors, GABA-A; D005680:gamma-Aminobutyric Acid; C567956:Adar protein, Drosophila; D000243:Adenosine Deaminase