1. AAV-delivered diacylglycerol kinase DGKk achieves long-term rescue of fragile X syndrome mouse model.
- Author
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Habbas K, Cakil O, Zámbó B, Tabet R, Riet F, Dembele D, Mandel JL, Hocquemiller M, Laufer R, Piguet F, and Moine H
- Subjects
- Animals, Diacylglycerol Kinase genetics, Diacylglycerol Kinase metabolism, Disease Models, Animal, Fragile X Mental Retardation Protein genetics, Fragile X Mental Retardation Protein metabolism, Mice, Mice, Knockout, Fragile X Syndrome genetics, Fragile X Syndrome metabolism, Fragile X Syndrome therapy
- Abstract
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., (© 2022 The Authors. Published under the terms of the CC BY 4.0 license.)
- Published
- 2022
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