RESUMEN
Fragile X syndrome (FXS) is an inherited neurologic disease caused by loss of fragile X mental retardation protein (FMRP), which is hypothesized to mediate negative regulation of mRNA translation at synapses. A prominent feature of FXS animal models is exaggerated signaling through group 1 metabotropic glutamate receptors (gp1 mGluRs), and therapeutic strategies to treat FXS are targeted mainly at gp1 mGluRs. Recent studies, however, indicate that a variety of receptor-mediated signal transduction pathways are dysregulated in FXS, suggesting that FMRP acts on a common downstream signaling molecule. Here, we show that deficiency of FMRP results in excess activity of phosphoinositide 3-kinase (PI3K), a downstream signaling molecule of many cell surface receptors. In Fmr1 knock-out neurons, excess synaptic PI3K activity can be reduced by perturbation of gp1 mGluR-mediated signaling. Remarkably, increased PI3K activity was also observed in FMRP-deficient non-neuronal cells in the absence of gp1 mGluRs. Here, we show that FMRP regulates the synthesis and synaptic localization of p110beta, the catalytic subunit of PI3K. In wild type, gp1 mGluR activation induces p110beta translation, p110beta protein expression, and PI3K activity. In contrast, both p110beta protein synthesis and PI3K activity are elevated and insensitive to gp1 mGluR stimulation in Fmr1 knock-out. This suggests that dysregulated PI3K signaling may underlie the synaptic impairments in FXS. In support of this hypothesis, we show that PI3K antagonists rescue three FXS-associated phenotypes: dysregulated synaptic protein synthesis, excess AMPA receptor internalization, and increased spine density. Targeting excessive PI3K activity might thus be a potent therapeutic strategy for FXS.
Asunto(s)
Inhibidores Enzimáticos/uso terapéutico , Síndrome del Cromosoma X Frágil/tratamiento farmacológico , Síndrome del Cromosoma X Frágil/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Subunidades de Proteína/metabolismo , Análisis de Varianza , Animales , Células Cultivadas , Fosfatidilinositol 3-Quinasa Clase I , Dendritas/metabolismo , Modelos Animales de Enfermedad , Embrión de Mamíferos , Inhibidores Enzimáticos/farmacología , Antagonistas de Aminoácidos Excitadores/farmacología , Proteína de la Discapacidad Intelectual del Síndrome del Cromosoma X Frágil/genética , Síndrome del Cromosoma X Frágil/genética , Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Regulación Enzimológica de la Expresión Génica/genética , Proteínas Fluorescentes Verdes/genética , Hipocampo/citología , Humanos , Inmunoprecipitación/métodos , Proteínas Luminiscentes/genética , Metoxihidroxifenilglicol/análogos & derivados , Metoxihidroxifenilglicol/farmacología , Ratones , Ratones Noqueados , Modelos Biológicos , Neuronas/metabolismo , Neuronas/ultraestructura , Fosfatidilinositol 3-Quinasas/genética , Subunidades de Proteína/genética , ARN Mensajero/metabolismo , Receptores AMPA/metabolismo , Sinapsis/metabolismo , Sinaptosomas/efectos de los fármacos , Sinaptosomas/metabolismo , Transfección/métodos , Proteína Fluorescente RojaRESUMEN
Hereditary paraganglioma (PGL)-pheochromocytoma (PCC) syndrome is a genetic disorder caused by a mutation of the tumor suppressor gene SDHD that results in a predisposition for head and neck PGLs and PCCs. We present a case of a 33-year-old woman where F-FDG PET/CT showed areas of increased uptake in both the adrenal and cervical regions, consistent with PCCs and PGLs, respectively. Further imaging revealed that PCCs were I-MIBG avid, whereas the PGLs were In-octreotide avid. This demonstrates the varying sensitivities of different imaging modalities in regard to neuroendocrine tumors and the potential for treatment using multiple targeted therapies.