Article abstract
Nature Chemical Biology 4, 256 - 263 (2008)
Published online: 9 March 2008 | doi:10.1038/nchembio.78
Identification of small molecules rescuing fragile X syndrome phenotypes in Drosophila
Shuang Chang1, Steven M Bray1, Zigang Li2, Daniela C Zarnescu3, Chuan He2, Peng Jin1 & Stephen T Warren1,4
Abstract
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.
- Department of Human Genetics, Emory University School of Medicine, 615 Michael Street Suite 300, Atlanta, Georgia 30322, USA.
- Department of Chemistry, The University of Chicago, GCIS 319B, 929 East 57th Street, Chicago, Illinois 60637, USA.
- Department of Molecular and Cellular Biology, University of Arizona, Life Sciences South 425 P.O. Box 210106, Tucson, Arizona 85721, USA.
- Departments of Pediatrics and Biochemistry, Emory University School of Medicine, 615 Michael Street Suite 300, Atlanta, Georgia 30322, USA.
Correspondence to: Stephen T Warren1,4 e-mail: swarren@emory.edu
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