Chang Shuang, Bray Steven M, Li Zigang, Zarnescu Daniela C, He Chuan, Jin Peng, Warren Stephen T
Department of Human Genetics, Emory University School of Medicine, 615 Michael Street Suite 300, Atlanta, Georgia 30322, USA.
Nat Chem Biol. 2008 Apr;4(4):256-63. doi: 10.1038/nchembio.78. Epub 2008 Mar 9.
Fragile X syndrome is caused by the functional loss of the fragile X mental retardation 1 (FMR1) gene. Deletion of the FMR1 ortholog in Drosophila melanogaster (Fmr1) recapitulates many phenotypes associated with fragile X syndrome. We have discovered that Fmr1 mutant Drosophila die during development when reared on food containing increased levels of glutamate, which is consistent with the theory that FMR1 loss results in excess glutamate signaling. Using this lethal phenotype, we screened a chemical library of 2,000 compounds and identified nine molecules that rescued the lethality, including three that implicate the GABAergic inhibitory pathway. Indeed, GABA treatment rescued several known Fmr1 mutant phenotypes in flies, including mushroom bodies defects, excess Futsch translation and abnormal male courtship behavior. These data are consistent with GABAergic inhibition of the enhanced excitatory pathway in fragile X syndrome. In addition, our screen reveals that the muscarinic cholinergic receptors may have a role in fragile X syndrome in parallel to the GABAergic pathway. These results point to potential therapeutic approaches for treating fragile X syndrome.
脆性X综合征由脆性X智力低下1（FMR1）基因的功能丧失引起。果蝇（黑腹果蝇）中FMR1直系同源基因（Fmr1）的缺失重现了许多与脆性X综合征相关的表型。我们发现，当在含有较高水平谷氨酸的食物上饲养时，Fmr1突变果蝇在发育过程中死亡，这与FMR1缺失导致谷氨酸信号过量的理论一致。利用这种致死表型，我们筛选了一个包含2000种化合物的化学文库，并鉴定出9种能够挽救致死性的分子，其中3种涉及γ-氨基丁酸（GABA）能抑制途径。事实上，GABA处理挽救了果蝇中几种已知的Fmr1突变表型，包括蘑菇体缺陷、Futsch过度翻译和异常的雄性求偶行为。这些数据与GABA能抑制脆性X综合征中增强的兴奋性途径一致。此外，我们的筛选表明，毒蕈碱型胆碱能受体可能在脆性X综合征中与GABA能途径并行发挥作用。这些结果指出了治疗脆性X综合征的潜在治疗方法。
