AAV-delivered diacylglycerol kinase DGKk achieves long-term rescue of fragile X syndrome mouse model.
Fiche publication
Date publication
avril 2022
Journal
EMBO molecular medicine
Auteurs
Membres identifiés du Cancéropôle Est :
Pr MANDEL Jean-Louis
Tous les auteurs :
Habbas K, Cakil O, Zámbó B, Tabet R, Riet F, Dembele D, Mandel JL, Hocquemiller M, Laufer R, Piguet F, Moine H
Lien Pubmed
Résumé
Fragile X syndrome (FXS) is the most frequent form of familial intellectual disability. FXS results from the lack of the RNA-binding protein FMRP and is associated with the deregulation of signaling pathways downstream of mGluRI receptors and upstream of mRNA translation. We previously found that diacylglycerol kinase kappa (DGKk), a main mRNA target of FMRP in cortical neurons and a master regulator of lipid signaling, is downregulated in the absence of FMRP in the brain of Fmr1-KO mouse model. Here we show that adeno-associated viral vector delivery of a modified and FMRP-independent form of DGKk corrects abnormal cerebral diacylglycerol/phosphatidic acid homeostasis and FXS-relevant behavioral phenotypes in the Fmr1-KO mouse. Our data suggest that DGKk is an important factor in FXS pathogenesis and provide preclinical proof of concept that its replacement could be a viable therapeutic strategy in FXS.
Mots clés
AAV, FMRP, Fmr1-KO, Fragile X syndrome, diacylglycerol kinase
Référence
EMBO Mol Med. 2022 Apr 4;:e14649