RESUMEN
Palmitoylation is a reversible post-translational lipid modification that facilitates vesicular transport and subcellular localization of modified proteins. This process is catalyzed by ZDHHC enzymes that are implicated in several neurological and neurodevelopmental disorders. Loss-of-function mutations in ZDHHC9 have been identified in patients with X-linked intellectual disability (XLID) and associated with increased epilepsy risk. Loss of Zdhhc9 function in hippocampal cultures leads to shorter dendritic arbors and fewer inhibitory synapses, altering the ratio of excitatory-to-inhibitory inputs formed onto Zdhhc9-deficient cells. While Zdhhc9 promotes dendrite outgrowth through the palmitoylation of the GTPase Ras, it promotes inhibitory synapse formation through the palmitoylation of another GTPase, TC10. Zdhhc9 knockout mice exhibit seizure-like activity together with increased frequency and amplitude of both spontaneous and miniature excitatory and inhibitory postsynaptic currents. These findings present a plausible mechanism for how the loss of ZDHHC9 function may contribute to XLID and epilepsy.
Asunto(s)
Aciltransferasas/metabolismo , Dendritas/metabolismo , Genes Ligados a X/fisiología , Discapacidad Intelectual/metabolismo , Sinapsis/metabolismo , Aciltransferasas/genética , Animales , Células Cultivadas , Epilepsia/genética , Epilepsia/metabolismo , Genes Ligados a X/genética , Hipocampo/metabolismo , Humanos , Discapacidad Intelectual/genética , Lipoilación/genética , Lipoilación/fisiología , Ratones , Ratones Noqueados , Sinapsis/genética , Proteínas ras/metabolismo , Proteínas de Unión al GTP rho/genética , Proteínas de Unión al GTP rho/metabolismoRESUMEN
Protein palmitoylation is the most common post-translational lipid modification in the brain and is mediated by a family of 24 zDHHC enzymes. There has been growing interest in zDHHCs due to mounting evidence that these enzymes play key roles in the development and function of neuronal connections, and the fact that a number of zDHHCs have been associated with neurodevelopmental and neurodegenerative diseases. Loss-of-function variants in several zDHHCs, including zDHHC15, have been identified in patients with intellectual disabilities; however, the function of zDHHC15 in the brain has not been well studied. Here, we demonstrate that knocking down zDHHC15 in primary rat hippocampal cultures reduces dendritic outgrowth and arborization, as well as spine maturation. Moreover, knockdown of zDHHC15 reduces palmitoylation of PSD-95 and its trafficking into dendrites, resulting in an overall decrease in the density of excitatory synapses being formed onto mutant cells.