Metformin ameliorates core deficits in a mouse model of fragile X syndrome

doi:10.1038/nm.4335

. 2017 Jun;23(6):674-677.

doi: 10.1038/nm.4335. Epub 2017 May 15.

Metformin ameliorates core deficits in a mouse model of fragile X syndrome

Ilse Gantois^{1

2}, Arkady Khoutorsky^{1

2

3

4}, Jelena Popic^{1

2}, Argel Aguilar-Valles^{1

2

5

6}, Erika Freemantle^{5

6}, Ruifeng Cao^{1

2

7}, Vijendra Sharma^{1

2}, Tine Pooters^{8

9}, Anmol Nagpal^{1

2}, Agnieszka Skalecka^{1

2}, Vinh T Truong^{1

2}, Shane Wiebe^{1

2}, Isabelle A Groves^{8

9}, Seyed Mehdi Jafarnejad^{1

2}, Clément Chapat^{1

2}, Elizabeth A McCullagh¹⁰, Karine Gamache¹¹, Karim Nader¹¹, Jean-Claude Lacaille^{5

6}, Christos G Gkogkas^{8

9}, Nahum Sonenberg^{1

2}

Affiliations

¹ Department of Biochemistry, McGill University, Montréal, Québec, Canada.
² Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montréal, Québec, Canada.
³ Department of Anesthesia, McGill University, Montréal, Québec, Canada.
⁴ Alan Edwards Centre for Research on Pain, McGill University, Montréal, Québec, Canada.
⁵ Department of Neurosciences, Université de Montréal, Montréal, Québec, Canada.
⁶ Groupe de Recherche sur le Système Nerveux Central, Université de Montréal, Montréal, Québec, Canada.
⁷ Department of Biomedical Sciences, University of Minnesota Medical School, Duluth, Minnesota, USA.
⁸ Patrick Wild Centre, University of Edinburgh, Edinburgh, UK.
⁹ Centre for Integrative Physiology, University of Edinburgh, Edinburgh, UK.
¹⁰ Department of Physiology and Biophysics, School of Medicine, University of Colorado, Aurora, Colorado, USA.
¹¹ Department of Psychology, McGill University, Montréal, Québec, Canada.

PMID: 28504725
DOI: 10.1038/nm.4335

Free article

Metformin ameliorates core deficits in a mouse model of fragile X syndrome

Ilse Gantois et al. Nat Med. 2017 Jun.

Free article

. 2017 Jun;23(6):674-677.

doi: 10.1038/nm.4335. Epub 2017 May 15.

Authors

Affiliations

¹ Department of Biochemistry, McGill University, Montréal, Québec, Canada.
² Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montréal, Québec, Canada.
³ Department of Anesthesia, McGill University, Montréal, Québec, Canada.
⁴ Alan Edwards Centre for Research on Pain, McGill University, Montréal, Québec, Canada.
⁵ Department of Neurosciences, Université de Montréal, Montréal, Québec, Canada.
⁶ Groupe de Recherche sur le Système Nerveux Central, Université de Montréal, Montréal, Québec, Canada.
⁷ Department of Biomedical Sciences, University of Minnesota Medical School, Duluth, Minnesota, USA.
⁸ Patrick Wild Centre, University of Edinburgh, Edinburgh, UK.
⁹ Centre for Integrative Physiology, University of Edinburgh, Edinburgh, UK.
¹⁰ Department of Physiology and Biophysics, School of Medicine, University of Colorado, Aurora, Colorado, USA.
¹¹ Department of Psychology, McGill University, Montréal, Québec, Canada.

PMID: 28504725
DOI: 10.1038/nm.4335

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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Comment in

Neurodevelopmental disorders: Metformin - a therapeutic option for fragile X syndrome?
Wood H. Wood H. Nat Rev Neurol. 2017 Jul;13(7):384-385. doi: 10.1038/nrneurol.2017.82. Epub 2017 Jun 2. Nat Rev Neurol. 2017. PMID: 28574060 No abstract available.

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References

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[1] Neuron. 2012 Oct 18;76(2):325-37 - PubMed

[2] Neuron. 2012 Oct 18;76(2):325-37 - PubMed

[3] Cell Metab. 2014 Dec 2;20(6):953-66 - PubMed

[4] Cell Metab. 2014 Dec 2;20(6):953-66 - PubMed

[5] J Neurosci. 2014 Jul 23;34(30):9867-79 - PubMed

[6] J Neurosci. 2014 Jul 23;34(30):9867-79 - PubMed

[7] Neurosci Lett. 2014 Sep 5;579:145-50 - PubMed

[8] Neurosci Lett. 2014 Sep 5;579:145-50 - PubMed

[9] Nature. 2015 Dec 10;528(7581):262-6 - PubMed

[10] Nature. 2015 Dec 10;528(7581):262-6 - PubMed

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Metformin ameliorates core deficits in a mouse model of fragile X syndrome

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Metformin ameliorates core deficits in a mouse model of fragile X syndrome

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