Identification of small molecules rescuing fragile X syndrome phenotypes in Drosophila.
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.
Chang
Shuang
S
Department of Human Genetics, Emory University School of Medicine, 615 Michael Street Suite 300, Atlanta, Georgia 30322, USA.
Bray
Steven M
SM
Li
Zigang
Z
Zarnescu
Daniela C
DC
He
Chuan
C
Jin
Peng
P
Warren
Stephen T
ST
D000818:Animals; D004195:Disease Models, Animal; D004330:Drosophila / Q000235:genetics*; D029721:Drosophila Proteins / Q000187:drug effects / Q000235:genetics*; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005260:Female; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000187:drug effects / Q000235:genetics*; D005600:Fragile X Syndrome / Q000235:genetics*; D018698:Glutamic Acid / Q000494:pharmacology; D008297:Male; D008970:Molecular Weight; D009154:Mutation; D010641:Phenotype; D011725:Pyridines / Q000494:pharmacology; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics; D054852:Small Molecule Libraries / Q000138:chemical synthesis / Q000737:chemistry*; D005680:gamma-Aminobutyric Acid / Q000187:drug effects / Q000378:metabolism / Q000494:pharmacology
D029721:Drosophila Proteins; D051860:Fragile X Messenger Ribonucleoprotein 1; D018698:Glutamic Acid; D011725:Pyridines; D012333:RNA, Messenger; D054852:Small Molecule Libraries; D005680:gamma-Aminobutyric Acid; C467328:FMR1 protein, Drosophila; C121465:6-methyl-2-(phenylethynyl)pyridine