The ADAR RNA editing enzyme controls neuronal excitability in Drosophila melanogaster.
The ADAR RNA editing enzyme controls neuronal excitability in Drosophila melanogaster.
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DOI：
10.1093/nar/gkt909
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发表时间：
2014-01
影响因子：
14.9
通讯作者：
O'Connell MA
中科院分区：
文献类型：
--
作者：
Li X;Overton IM;Baines RA;Keegan LP;O'Connell MA
通过在前mRNA加工期间将特定腺苷碱基脱氨基化为肌苷的RNA编辑产生编辑的蛋白质同种型。RNA编辑在果蝇中比在脊椎动物中更普遍。编辑水平在变态时强烈上升，Adar 5G 1无效突变果蝇在数百个CNS转录物中缺乏编辑事件;突变果蝇的生存能力降低，运动严重缺陷和年龄依赖性神经变性。另一方面，在幼虫和蛹阶段普遍过度表达具有高酶活性的成虫dADAR亚型是致命的。利用这一点来筛选遗传修饰剂;通过减少剂量的Rdl（抗狄氏剂）（编码抑制性GABA受体亚基的基因）来挽救阿达尔过表达致死性。减少剂量的Gad 1基因编码的GABA合成酶也挽救了阿达尔过表达致死。果蝇Adar 5G 1突变体表型通过喂食GABA调节剂得到改善。我们证明，神经元的兴奋性与个别神经元中的d阿达尔表达水平有关; Adar过表达的幼虫运动神经元表现出降低的兴奋性，而Adar 5G 1无效突变体或靶向阿达尔敲低运动神经元表现出增加的兴奋性。GABA抑制信号在人类癫痫和自闭症条件下受损，脊椎动物ADAR可能对神经元兴奋性具有相关的进化保守控制。
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 Adar5G1 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 Adar5G1 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 Adar5G1 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.
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影响因子：
11.4
作者：
Keegan, LP;Brindle, J;O'Connell, MA
通讯作者：
O'Connell, MA
影响因子：
12.3
作者：
Cook RK;Christensen SJ;Deal JA;Coburn RA;Deal ME;Gresens JM;Kaufman TC;Cook KR
通讯作者：
Cook KR
影响因子：
14.9
作者：
Keegan LP;McGurk L;Palavicini JP;Brindle J;Paro S;Li X;Rosenthal JJ;O'Connell MA
通讯作者：
O'Connell MA
影响因子：
56.9
作者：
Hoopengardner, B;Bhalla, T;Reenan, R
通讯作者：
Reenan, R
影响因子：
64.8
作者：
Graveley BR;Brooks AN;Carlson JW;Duff MO;Landolin JM;Yang L;Artieri CG;van Baren MJ;Boley N;Booth BW;Brown JB;Cherbas L;Davis CA;Dobin A;Li R;Lin W;Malone JH;Mattiuzzo NR;Miller D;Sturgill D;Tuch BB;Zaleski C;Zhang D;Blanchette M;Dudoit S;Eads B;Green RE;Hammonds A;Jiang L;Kapranov P;Langton L;Perrimon N;Sandler JE;Wan KH;Willingham A;Zhang Y;Zou Y;Andrews J;Bickel PJ;Brenner SE;Brent MR;Cherbas P;Gingeras TR;Hoskins RA;Kaufman TC;Oliver B;Celniker SE
通讯作者：
Celniker SE