FMRP controls diacylglycerol-dependent neuronal activity by mediating m6A-regulated translation efficiency
Cakil, O.; Zambo, B.; Maroilley, T.; Drouot, N.; Petrova, A.; Negroni, L.; Gogl, G.; PITON, A.; Moine, H.
Show abstract
Fragile X syndrome (FXS), a leading inherited cause of intellectual developmental disorder and autism, results from loss of the RNA-binding protein FMRP. Loss of FMRP causes excessive neuronal protein synthesis contributing to widespread functional disturbances, yet the mechanisms linking FMRP to specific mRNA targets remain unclear. We show that FMRP promotes translation of the brain mRNA DGK{kappa} by binding mA-modified repetitive RNA motifs, thereby relieving a translational block encoded within its sequence. FMRP loss sharply reduces neuronal DGK{kappa}, and DGK{kappa} depletion alone reproduces hallmark FXS phenotypes, including hyperactivity, compulsive behavior, overgrowth, dendritic spine abnormalities, overactivated diacylglycerol signaling and increased protein synthesis. These findings identify DGK{kappa} as a key effector of FMRP function and establish a regulatory axis where mA RNA modification modulates neuronal translation. This work defines new principles of translational control in neurodevelopmental disorders and positions DGK{kappa} as a central driver of FXS pathogenesis.
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