Open AccessAAV‐delivered diacylglycerol kinase DGKk achieves long‐term rescue of fragile X syndrome mouse model
Author(s) -
Habbas Karima,
Cakil Oktay,
Zámbó Boglárka,
Tabet Ricardos,
Riet Fabrice,
Dembele Doulaye,
Mandel JeanLouis,
Hocquemiller Michaël,
Laufer Ralph,
Piguet Françoise,
Moine Hervé
Publication year - 2022
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.15252/emmm.202114649
Subject(s) - diacylglycerol kinase , fragile x syndrome , fmr1 , biology , microbiology and biotechnology , regulator , neuroscience , rna binding protein , kinase , messenger rna , protein kinase c , genetics , gene , fragile x
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.