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Identification of small molecules rescuing fragile X syndrome phenotypes in Drosophila

Nature Chemical Biology volume 4, pages 256263 (2008) | Download Citation

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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.

  • Compound

    2-Methyl-6-(phenylethynyl)pyridine

  • Compound

    (S)-2-Aminopentanedioic acid dianion

  • Compound

    3-Hydroxybenzylhydrazine dihydrochloride

  • Compound

    N-Acetyl-L-cysteine

  • Compound

    3-Piperidinecarboxylic acid

  • Compound

    2-Amino-1-methyl-2-imidazolin-4-one

  • Compound

    4-Chloro-3,5-dimethylphenol

  • Compound

    Ergonovine maleate

  • Compound

    Pilocarpine nitrate salt

  • Compound

    3,4-Bis(4-hydroxyphenyl)-2,4-hexadiene

  • Compound

    2-(4-[2-Chloro-1,2-diphenylethenyl]phenoxy)-N,N-diethylethanamine

  • Compound

    gamma-Aminobutyric acid

  • Compound

    2-Hydroxymethyl-5-hydroxy-gamma-pyrone

  • Compound

    3-(2′-Aminobenzhydryloxy)tropane

  • Compound

    2-Aminoacetophenone hydrochloride

  • Compound

    2-(3,4-Dihydroxyphenyl)ethylamine hydrochloride

  • Compound

    Reserpine

  • Compound

    [S-(R*,R*)]-[3-[[1-(3,4-Dichlorophenyl)ethyl]amino]-2-h ydroxypropyl](cyclohexylmethyl) phosphinic acid

  • Compound

    (−)-Scopolamine hydrobromide trihydrate

  • Compound

    (−)-Bicuculline methiodide

  • Compound

    (S)-Methyl 1-[5-(4-amino-4-carboxybutanoyl)]-7-nitroindoline-5-acetate hydrate

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Acknowledgements

We thank S. L'Hernault, T. Kroft, H. Liu and C. Yu for assistance. We thank Y. Feng and the members of the Warren and Jin labs for their assistance and critical comments. We thank T.A. Jongens (University of Pennsylvania) for providing the transgenic fly carrying a copy of the Fmr1 transgene. We also thank the National Institute of Child Health and Human Development (NICHD) Developmental Studies Hybridoma Bank at the University of Iowa for antibodies. S.C. is supported by a Fragile X Research Foundation (FRAXA) postdoctoral grant, and S.M.B. is supported by a Frederick Gardner Cottrell Fellowship at Emory University. This work was supported by US National Institutes of Health grants HD020521 and HD24064 to S.T.W. and by the Colonial Oaks Foundation.

Author information

Affiliations

  1. Department of Human Genetics, Emory University School of Medicine, 615 Michael Street Suite 300, Atlanta, Georgia 30322, USA.

    • Shuang Chang
    • , Steven M Bray
    • , Peng Jin
    •  & Stephen T Warren
  2. Department of Chemistry, The University of Chicago, GCIS 319B, 929 East 57th Street, Chicago, Illinois 60637, USA.

    • Zigang Li
    •  & Chuan He
  3. Department of Molecular and Cellular Biology, University of Arizona, Life Sciences South 425 P.O. Box 210106, Tucson, Arizona 85721, USA.

    • Daniela C Zarnescu
  4. Departments of Pediatrics and Biochemistry, Emory University School of Medicine, 615 Michael Street Suite 300, Atlanta, Georgia 30322, USA.

    • Stephen T Warren

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Contributions

S.C. designed and performed experiments, analyzed data and wrote the manuscript; S.M.B. performed experiments, analyzed data and revised the manuscript; D.C.Z. and P.J. made initial observations; Z.L. and C.H. conducted the chemical analysis; P.J. designed the research and provided fly strains; S.T.W. designed and supervised the research, wrote and revised the manuscript and obtained funding for the research.

Competing interests

S.T.W. declares he is chair of the Scientific Advisory Board of Seaside Therapeutics, Inc. The remaining authors declare that they have no competing financial interests.

Corresponding author

Correspondence to Stephen T Warren.

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https://doi.org/10.1038/nchembio.78

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