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 journalArticle

198 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)256-263
Number of pages8
JournalNature Chemical Biology
Volume4
Issue number4
DOIs
StatePublished - Apr 2008

Fingerprint

Fragile X Syndrome
Drosophila
Phenotype
Intellectual Disability
Glutamic Acid
Mushroom Bodies
Small Molecule Libraries
Courtship
Cholinergic Receptors
Muscarinic Receptors
Drosophila melanogaster
Diptera
gamma-Aminobutyric Acid
Food
Genes

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology

Cite this

Identification of small molecules rescuing fragile X syndrome phenotypes in Drosophila. / Chang, Shuang; Bray, Steven M.; Li, Zigang; Zarnescu, Daniela C; He, Chuan; Jin, Peng; Warren, Stephen T.

In: Nature Chemical Biology, Vol. 4, No. 4, 04.2008, p. 256-263.

Research output: Contribution to journalArticle

Chang, Shuang ; Bray, Steven M. ; Li, Zigang ; Zarnescu, Daniela C ; He, Chuan ; Jin, Peng ; Warren, Stephen T. / Identification of small molecules rescuing fragile X syndrome phenotypes in Drosophila. In: Nature Chemical Biology. 2008 ; Vol. 4, No. 4. pp. 256-263.
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