| First Author | Habbas K | Year | 2022 |
| Journal | EMBO Mol Med | Volume | 14 |
| Issue | 5 | Pages | e14649 |
| PubMed ID | 35373916 | Mgi Jnum | J:324811 |
| Mgi Id | MGI:7277914 | Doi | 10.15252/emmm.202114649 |
| Citation | Habbas K, et al. (2022) AAV-delivered diacylglycerol kinase DGKk achieves long-term rescue of fragile X syndrome mouse model. EMBO Mol Med 14(5):e14649 |
| abstractText | 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. |
