Identification of small molecules rescuing fragile X syndrome phenotypes in Drosophila

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Disease Models, Animal
  • Drosophila / genetics*
  • Drosophila Proteins / drug effects
  • Drosophila Proteins / genetics*
  • Drug Evaluation, Preclinical / methods
  • Female
  • Fragile X Mental Retardation Protein / drug effects
  • Fragile X Mental Retardation Protein / genetics*
  • Fragile X Syndrome / genetics*
  • Glutamic Acid / pharmacology
  • Male
  • Molecular Weight
  • Mutation
  • Phenotype
  • Pyridines / pharmacology
  • RNA, Messenger / drug effects
  • RNA, Messenger / genetics
  • Small Molecule Libraries / chemical synthesis
  • Small Molecule Libraries / chemistry*
  • gamma-Aminobutyric Acid / drug effects
  • gamma-Aminobutyric Acid / metabolism
  • gamma-Aminobutyric Acid / pharmacology


  • Drosophila Proteins
  • FMR1 protein, Drosophila
  • Pyridines
  • RNA, Messenger
  • Small Molecule Libraries
  • Fragile X Mental Retardation Protein
  • Glutamic Acid
  • gamma-Aminobutyric Acid
  • 6-methyl-2-(phenylethynyl)pyridine

Associated data

  • PubChem-Substance/47213189
  • PubChem-Substance/47213190
  • PubChem-Substance/47213191
  • PubChem-Substance/47213192
  • PubChem-Substance/47213193
  • PubChem-Substance/47213194
  • PubChem-Substance/47213195
  • PubChem-Substance/47213196
  • PubChem-Substance/47213197
  • PubChem-Substance/47213198
  • PubChem-Substance/47213199
  • PubChem-Substance/47213200
  • PubChem-Substance/47213201
  • PubChem-Substance/47213202
  • PubChem-Substance/47213203
  • PubChem-Substance/47213204
  • PubChem-Substance/47213205
  • PubChem-Substance/47213206
  • PubChem-Substance/47213207
  • PubChem-Substance/47213208
  • PubChem-Substance/47213209