Abstract
Fragile X syndrome (FXS) is the leading monogenic cause of autism spectrum disorders (ASD). Trinucleotide repeat expansions in FMR1 abolish FMRP expression, leading to hyperactivation of ERK and mTOR signaling upstream of mRNA translation. Here we show that metformin, the most widely used drug for type 2 diabetes, rescues core phenotypes in Fmr1−/y mice and selectively normalizes ERK signaling, eIF4E phosphorylation and the expression of MMP-9. Thus, metformin is a potential FXS therapeutic.
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Acknowledgements
This work is supported by the FRAXA Research Foundation, Brain Canada/FNC, a CIHR foundation grant (FDN-148423) and Brain & Behavior Research Foundation grants (24365) to N.S.; a Wellcome Trust/Royal Society Sir Henry Dale grant (107687/Z/15/Z) to C.G.G.; the Canada Research Chair Program (950-231066) to J.-C.L.; and a Brain Canada/NeuroDevNet Postdoctoral Training Award to J.P.
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I.G., A.K. and J.P. designed the experiments, performed data analysis and wrote the manuscript. I.G., A.K., J.P., A.A.-V., E.F., R.C., V.S., T.P., A.N., S.W., S.M.J., C.C., E.A.M. and C.G.G. designed and carried out experiments. A.S., V.T.T., I.A.G. and K.G. assisted with experiments. K.N. supervised the project. J.-C.L., C.G.G. and N.S. supervised the project, designed experiments and edited the manuscript. All authors revised the manuscript.
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Gantois, I., Khoutorsky, A., Popic, J. et al. Metformin ameliorates core deficits in a mouse model of fragile X syndrome. Nat Med 23, 674–677 (2017). https://doi.org/10.1038/nm.4335
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DOI: https://doi.org/10.1038/nm.4335
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