| Identification of small molecules rescuing fragile X syndrome phenotypes in Drosophila. | |
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MedLine Citation:
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PMID: 18327252 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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Shuang Chang; Steven M Bray; Zigang Li; Daniela C Zarnescu; Chuan He; Peng Jin; Stephen T Warren |
Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2008-03-09 |
Journal Detail:
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Title: Nature chemical biology Volume: 4 ISSN: 1552-4469 ISO Abbreviation: Nat. Chem. Biol. Publication Date: 2008 Apr |
Date Detail:
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Created Date: 2008-03-18 Completed Date: 2008-09-15 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 101231976 Medline TA: Nat Chem Biol Country: United States |
Other Details:
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Languages: eng Pagination: 256-63 Citation Subset: IM |
Affiliation:
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Department of Human Genetics, Emory University School of Medicine, 615 Michael Street Suite 300, Atlanta, Georgia 30322, USA. |
| Data Bank Information | |
Bank Name/Acc. No.:
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PubChem-Substance/47213189; 47213190; 47213191; 47213192; 47213193; 47213194; 47213195; 47213196; 47213197; 47213198; 47213199; 47213200; 47213201; 47213202; 47213203; 47213204; 47213205; 47213206; 47213207; 47213208; 47213209 |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Disease Models, Animal Drosophila / genetics* Drosophila Proteins / drug effects, genetics* Drug Evaluation, Preclinical / methods Female Fragile X Mental Retardation Protein / drug effects, genetics* Fragile X Syndrome / genetics* Glutamic Acid / pharmacology Male Molecular Weight Mutation Phenotype Pyridines / pharmacology RNA, Messenger / drug effects, genetics Small Molecule Libraries / chemical synthesis, chemistry* gamma-Aminobutyric Acid / drug effects, metabolism, pharmacology |
| Grant Support | |
ID/Acronym/Agency:
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HD020521/HD/NICHD NIH HHS; HD24064/HD/NICHD NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/6-methyl-2-(phenylethynyl)pyridine; 0/Drosophila Proteins; 0/FMR1 protein, Drosophila; 0/Pyridines; 0/RNA, Messenger; 0/Small Molecule Libraries; 139135-51-6/Fragile X Mental Retardation Protein; 56-12-2/gamma-Aminobutyric Acid; 56-86-0/Glutamic Acid |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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