AAV‐delivered diacylglycerol kinase DGKk achieves long‐term rescue of fragile X syndrome mouse model
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.
Domains
Life Sciences [q-bio]
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2022 EMBO Mol Med - Habbas - AAV%u2010delivered diacylglycerol kinase DGKk achieves long%u2010term rescue of fragile X syndrome.pdf (1.23 Mo)
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