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

Ilse Gantois; Arkady Khoutorsky; Jelena Popic; Argel Aguilar-Valles; Erika Freemantle; Ruifeng Cao; Vijendra Sharma; Tine Pooters; Anmol Nagpal; Agnieszka Skalecka; Vinh T Truong; Shane Wiebe; Isabelle A Groves; Seyed Mehdi Jafarnejad; Clément Chapat; Elizabeth A McCullagh; Karine Gamache; Karim Nader; Jean-Claude Lacaille; Christos G Gkogkas; Nahum Sonenberg

doi:10.1038/nm.4335

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

Nat Med. 2017 Jun;23(6):674-677. doi: 10.1038/nm.4335. Epub 2017 May 15.

Authors

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

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.

MeSH terms

Animals
Behavior, Animal / drug effects*
Disease Models, Animal
Eukaryotic Initiation Factor-4E / drug effects*
Eukaryotic Initiation Factor-4E / metabolism
Fragile X Mental Retardation Protein / genetics*
Fragile X Syndrome / genetics*
Fragile X Syndrome / metabolism
Fragile X Syndrome / physiopathology
Hypoglycemic Agents / pharmacology*
MAP Kinase Signaling System / drug effects*
Male
Matrix Metalloproteinase 9 / drug effects*
Matrix Metalloproteinase 9 / metabolism
Metformin / pharmacology*
Mice
Mice, Knockout
Phosphorylation / drug effects
RNA, Messenger / drug effects
RNA, Messenger / metabolism
Social Behavior*
Trinucleotide Repeat Expansion

Substances

Eukaryotic Initiation Factor-4E
Fmr1 protein, mouse
Hypoglycemic Agents
RNA, Messenger
Fragile X Mental Retardation Protein
Metformin
Matrix Metalloproteinase 9
Mmp9 protein, mouse