Reference

M. Segarra-Mondejar, S. Casellas-Díaz, M. Ramiro-Pareta, C. Müller-Sánchez, A. Martorell-Riera, I. Hermelo, M. Reina, J. Aragonés, O. M. Martínez-Estrada, and F. X. Soriano, “Synaptic activity-induced glycolysis facilitates membrane lipid provision and neurite outgrowth.,” EMBO J., p. e97368, Apr. 2018. EMBJOJ cover April 2018

Authors

Marc Segarra-Mondejar , Sergi Casellas-Díaz, Marina Ramiro-Pareta, Alejandro Martorell-Riera , Ismaïl Hermelo-Akhtar, Manuel Reina, Julián Aragonés, Ofelia M. Martínez-Estrada, Francesc X. Soriano

[resumenThe formation of neurites is an important process affecting the cognitive abilities of an organism. Neurite growth requires the addition of new membranes, but the metabolic remodeling necessary to supply lipids for membrane expansion is poorly understood. Here, we show that synaptic activity, one of the most important inducers of neurite growth, transcriptionally regulates the expression of neuronal glucose transporter Glut3 and rate‐limiting enzymes of glycolysis, resulting in enhanced glucose uptake and metabolism that is partly used for lipid synthesis. Mechanistically, CREB regulates the expression of Glut3 and Siah2, the latter and LDH activity promoting the normoxic stabilization of HIF‐1α that regulates the expression of rate‐limiting genes of glycolysis. The expression of dominant‐negative HIF‐1α or Glut3 knockdown blocks activity‐dependent neurite growth in vitro while pharmacological inhibition of the glycolysis and specific ablation of HIF‐1α in early postnatal mice impairs the neurite architecture. These results suggest that the manipulation of neuronal glucose metabolism could be used to treat some brain developmental disorders.

[/resumen]

 

Description

La formación de nuevas neuritas es un proceso clave para el correcto desarrollo del sistema nervioso. El crecimiento neurítico requiere la generación de nuevas membranas. No obstante, los cambios metabólicos que hacen posible la síntesis de estas han sido poco estudiados. En este artículo, mostramos que la actividad sináptica, uno de los principales inductores del crecimiento neuronal, incrementa el transporte de glucosa y su metabolismo con el objetivo de promover la síntesis de lípidos destinados al crecimiento neurítico. La inducción de ambos procesos se da a nivel transcripcional. La activación del factor de transcripción CREB activa la expresión de Glut 3, el principal transportador de glucosa en neuronas, y de Siah2, implicado en la estabilización de HIF-1a. HIF-1a, por último, es el encargado de inducir la transcripción de los genes limitantes del metabolismo de la glucosa. Estos resultados abren una nueva vía en el tratamiento de enfermedades que afectan al desarrollo del sistema nervioso central.

 

 

Foto grupomayo2018

 

REFERENCIA DEL GRUPO INVESTIGADOR

El grupo dirigido por el Dr. Francesc X. Soriano se centra en el estudio de los mecanismos moleculares que determinan la muerte o la supervivencia neuronal. A pesar de la gran variedad de enfermedades neurodegenerativas la mayoría de ellas presentan problemas en la función mitocondrial. En nuestro grupo estudiamos cómo la viabilidad neuronal se ve afectado por cambios en la dinámica mitocondrial. Por otro lado, es bien sabido que la actividad sináptica juega un papel clave en neuroprotección. Por lo tanto tratamos de determinar qué vías pro-supervivencia son reguladas por la actividad sináptica y como podemos inducirlas para tratar enfermedades neurodegenerativas.

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