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 foun...
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Springer Nature
2022-04-01
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| Series: | EMBO Molecular Medicine |
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| Online Access: | https://doi.org/10.15252/emmm.202114649 |
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| author | Karima Habbas Oktay Cakil Boglárka Zámbó Ricardos Tabet Fabrice Riet Doulaye Dembele Jean‐Louis Mandel Michaël Hocquemiller Ralph Laufer Françoise Piguet Hervé Moine |
| author_facet | Karima Habbas Oktay Cakil Boglárka Zámbó Ricardos Tabet Fabrice Riet Doulaye Dembele Jean‐Louis Mandel Michaël Hocquemiller Ralph Laufer Françoise Piguet Hervé Moine |
| author_sort | Karima Habbas |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-f6fe6fea1bab4023b24b4f87b67b8131 |
| institution | Kabale University |
| issn | 1757-4676 1757-4684 |
| language | English |
| publishDate | 2022-04-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj-art-f6fe6fea1bab4023b24b4f87b67b81312025-08-20T03:46:13ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842022-04-0114511510.15252/emmm.202114649AAV‐delivered diacylglycerol kinase DGKk achieves long‐term rescue of fragile X syndrome mouse modelKarima Habbas0Oktay Cakil1Boglárka Zámbó2Ricardos Tabet3Fabrice Riet4Doulaye Dembele5Jean‐Louis Mandel6Michaël Hocquemiller7Ralph Laufer8Françoise Piguet9Hervé Moine10Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Département de Médecine Translationelle et Neurogénétique, Centre National de la Recherche Scientifique (CNRS UMR7104), Institut National de la Santé et de la Recherche Médicale (INSERM U1258), Université de StrasbourgInstitut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Département de Médecine Translationelle et Neurogénétique, Centre National de la Recherche Scientifique (CNRS UMR7104), Institut National de la Santé et de la Recherche Médicale (INSERM U1258), Université de StrasbourgInstitut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Département de Médecine Translationelle et Neurogénétique, Centre National de la Recherche Scientifique (CNRS UMR7104), Institut National de la Santé et de la Recherche Médicale (INSERM U1258), Université de StrasbourgInstitut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Département de Médecine Translationelle et Neurogénétique, Centre National de la Recherche Scientifique (CNRS UMR7104), Institut National de la Santé et de la Recherche Médicale (INSERM U1258), Université de StrasbourgInstitut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), PHENOMIN‐ICS, Centre National de la Recherche Scientifique (CNRS UMR7104), Institut National de la Santé et de la Recherche Médicale (INSERM U1258), Université de StrasbourgInstitut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Département de Médecine Translationelle et Neurogénétique, Centre National de la Recherche Scientifique (CNRS UMR7104), Institut National de la Santé et de la Recherche Médicale (INSERM U1258), Université de StrasbourgInstitut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Département de Médecine Translationelle et Neurogénétique, Centre National de la Recherche Scientifique (CNRS UMR7104), Institut National de la Santé et de la Recherche Médicale (INSERM U1258), Université de StrasbourgLysogeneLysogeneNeuroGenCell, INSERM U1127, Paris Brain Institute (ICM), Sorbonne University, CNRS, AP‐HP, University Hospital Pitié‐SalpêtrièreInstitut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Département de Médecine Translationelle et Neurogénétique, Centre National de la Recherche Scientifique (CNRS UMR7104), Institut National de la Santé et de la Recherche Médicale (INSERM U1258), Université de StrasbourgAbstract 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.https://doi.org/10.15252/emmm.202114649AAVdiacylglycerol kinaseFmr1‐KOFMRPFragile X syndrome |
| spellingShingle | Karima Habbas Oktay Cakil Boglárka Zámbó Ricardos Tabet Fabrice Riet Doulaye Dembele Jean‐Louis Mandel Michaël Hocquemiller Ralph Laufer Françoise Piguet Hervé Moine AAV‐delivered diacylglycerol kinase DGKk achieves long‐term rescue of fragile X syndrome mouse model EMBO Molecular Medicine AAV diacylglycerol kinase Fmr1‐KO FMRP Fragile X syndrome |
| title | AAV‐delivered diacylglycerol kinase DGKk achieves long‐term rescue of fragile X syndrome mouse model |
| title_full | AAV‐delivered diacylglycerol kinase DGKk achieves long‐term rescue of fragile X syndrome mouse model |
| title_fullStr | AAV‐delivered diacylglycerol kinase DGKk achieves long‐term rescue of fragile X syndrome mouse model |
| title_full_unstemmed | AAV‐delivered diacylglycerol kinase DGKk achieves long‐term rescue of fragile X syndrome mouse model |
| title_short | AAV‐delivered diacylglycerol kinase DGKk achieves long‐term rescue of fragile X syndrome mouse model |
| title_sort | aav delivered diacylglycerol kinase dgkk achieves long term rescue of fragile x syndrome mouse model |
| topic | AAV diacylglycerol kinase Fmr1‐KO FMRP Fragile X syndrome |
| url | https://doi.org/10.15252/emmm.202114649 |
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