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

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

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

Article in English | MEDLINE | ID: mdl-28504725

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.

Subject(s)

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

ABSTRACT

Subject(s)

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