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• W2955710329 abstract "ABSTRACT Fragile X syndrome (FXS), caused by mutations in fragile X mental retardation 1 gene ( FMR1 ), is a prevailing genetic disorder of intellectual disability and autism. Currently, there is no efficacious medication for FXS. Here, we use transcriptome landscape as a holistic molecular phenotype/endpoint to identify potential therapeutic intervention. Throug h in silico screening with public gene signature database, computational analysis of transcriptome profile in Fmr1 knockout (KO) neurons predicts therapeutic value of an FDA-approved drug trifluoperazine. Through experimental validation, we find that systemic administration of low dose trifluoperazine at 0.05 mg/kg attenuates multiple FXS- and autism-related behavioral symptoms. Moreover, computational analysis of transcriptome alteration caused by trifluoperazine suggests a new mechanism of action against PI3K (Phosphatidylinositol-4,5-bisphosphate 3-kinase) activity. Consistently, trifluoperazine suppresses PI3K activity and its down-stream targets Akt (protein kinase B) and S6K1 (S6 kinase 1) in neurons. Further, trifluoperazine normalizes the aberrantly elevated activity of Akt and S6K1 and enhanced protein synthesis in FXS mouse. In conclusion, our data demonstrate promising value of gene signature-based computation in identification of therapeutic strategy and repurposing drugs for neurological disorders, and suggest trifluoperazine as a potential practical treatment for FXS." @default.
• W2955710329 created "2019-07-12" @default.
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• W2955710329 date "2019-06-27" @default.
• W2955710329 modified "2023-09-27" @default.
• W2955710329 title "Computational analysis of transcriptome signature repurposes low dose trifluoperazine for the treatment of fragile X syndrome in mouse model" @default.
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• W2955710329 doi "https://doi.org/10.1101/683169" @default.
• W2955710329 hasPublicationYear "2019" @default.
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