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AAV-delivered diacylglycerol kinase DGKk achieves long-term rescue of fragile X syndrome mouse model.
- Source :
-
EMBO molecular medicine [EMBO Mol Med] 2022 May 09; Vol. 14 (5), pp. e14649. Date of Electronic Publication: 2022 Apr 04. - Publication Year :
- 2022
-
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.<br /> (© 2022 The Authors. Published under the terms of the CC BY 4.0 license.)
- 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
Subjects
Details
- Language :
- English
- ISSN :
- 1757-4684
- Volume :
- 14
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- EMBO molecular medicine
- Publication Type :
- Academic Journal
- Accession number :
- 35373916
- Full Text :
- https://doi.org/10.15252/emmm.202114649