Identification of small molecules rescuing fragile X syndrome phenotypes in Drosophila

Shuang Chang, Steven M. Bray, Zigang Li, Daniela C. Zarnescu, Chuan He, Peng Jin, Stephen T. Warren

Research output: Contribution to journalArticlepeer-review

224 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)256-263
Number of pages8
JournalNature chemical biology
Issue number4
StatePublished - Apr 2008

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology


Dive into the research topics of 'Identification of small molecules rescuing fragile X syndrome phenotypes in Drosophila'. Together they form a unique fingerprint.

Cite this