Identification of small molecules rescuing fragile X syndrome phenotypes in Drosophila
Identification of small molecules rescuing fragile X syndrome phenotypes in Drosophila
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DOI：
10.1038/nchembio.78
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发表时间：
2008-04-01
影响因子：
14.8
通讯作者：
Warren, Stephen T.
中科院分区：
文献类型：
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作者：
Chang, Shuang;Bray, Steven M.;Warren, Stephen T.
脆性X综合征是由脆性X智力低下1（FMR 1）基因的功能丧失引起的。黑腹果蝇FMR 1同源基因（Fmr 1）的缺失重现了许多与脆性X综合征相关的表型。我们已经发现，Fmr 1突变果蝇在发育过程中死亡时，饲养的食物中含有增加水平的谷氨酸，这是与FMR 1损失导致过量的谷氨酸信号的理论相一致。使用这种致死表型，我们筛选了2,000种化合物的化学文库，并鉴定了9种挽救致死性的分子，包括3种涉及GABA能抑制途径的分子。事实上，GABA治疗挽救了苍蝇中几种已知的Fmr 1突变表型，包括蘑菇体缺陷，过量的Futsch翻译和异常的雄性求偶行为。这些数据与脆性X综合征中GABA能抑制增强的兴奋性通路一致。此外，我们的筛选揭示了毒蕈碱胆碱能受体可能在脆性X综合征中与GABA能通路平行发挥作用。这些结果指出了治疗脆性X综合征的潜在治疗方法。
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.