Relevancia de los rafts en la polaridad neuronale implicancias de sus alteraciones en la enfermedad de Niemann-Pick tipo A
Palabras clave:
rafts, polaridad neuronal, esfingomielina, endocitosis, Niemann-Pick Tipo AResumen
Una de las principales características de las neuronas es su extremada polaridad. La diferenciación tanto morfológica como molecular de axones y dendritas es necesaria para la función neuronal. Defectos en esta diferenciación pueden contribuir a la patología de distintas enfermedades neurológicas. Sin embargo, los mecanismos que establecen y mantienen la polaridad neuronal y sus implicancias patológicas no están completamente resueltos. En esta tesis doctoral, nos hemos centrado en investigar la contribución a la polaridad neuronal de los dominios de membrana enriquecidos en colesterol y esfingolípidos, los llamados rafts. Describimos que los rafts son esenciales para la distribución axonal de moléculas como la proteína del Prion (PrPC) o el gangliósido GM1 en neuronas hipocampales maduras y analizamos la contribución a este proceso de sus componentes lipídicos mayoritarios: el colesterol y los esfingolípidos. Los estudios realizados apuntan al control de la endocitosis dendrítica como factor clave para la polarización axonal de moléculas de rafts. Además, caracterizamos las alteraciones de los rafts en el cerebro y neuronas de un modelo murino para la enfermedad de Niemann-Pick tipo A (NPA). La actividad deficiente de la esfingomielinidasa ácida (ASM), que causa la enfermedad, lleva a la acumulación de la esfingomielina (SM) en la membrana plasmática neuronal. Demostramos que al alterar los rafts esta acumulación reduce la endocitosis dendrítica de moléculas como PrPC y GM1 impidiendo la unión a membrana de la GTPasa RhoA. Esto tiene como consecuencia la distribución no polarizada de estas moléculas que aparecen de forma anómala en las dendritas de neuronas de ratones ASMko. La modulación experimental de los niveles de SM promueve o previene este fenotipo. En conjunto, los resultados obtenidos aportan información sobre los mecanismos de polaridad neuronal y sugieren que defectos en la polaridad pueden jugar un relevante papel patológico en NPA.Descargas
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