EMBO Mol Med. 2011 Aug 29. doi: 10.1002/emmm.201100174.


Valles-Ortega J*, Duran J*, Garcia-Rocha M, Bosch C, Saez I, Pujadas L, Serafin A, Cañas X, Soriano E, Delgado-García JM, Gruart A, Guinovart JJ. * Coautores


Lafora disease (LD) is caused by mutations in either the laforin or malin gene. The hallmark of the disease is the accumulation of polyglucosan inclusions called Lafora Bodies (LBs). Malin knockout (KO) mice present polyglucosan accumulations in several brain areas, as do patients of LD. These structures are abundant in the cerebellum and hippocampus. Here, we report a large increase in glycogen synthase (GS) in these mice, in which the enzyme accumulates in LBs. Our study focused on the hippocampus where, under physiological conditions, astrocytes and parvalbumin-positive (PV(+) ) interneurons expressed GS and malin. Although LBs have been described only in neurons, we found this polyglucosan accumulation in the astrocytes of the KO mice. They also had LBs in the soma and some processes of PV(+) interneurons. This phenomenon was accompanied by the progressive loss of these neuronal cells and, importantly, neurophysiological alterations potentially related to impairment of hippocampal function. Our results emphasize the relevance of the laforin-malin complex in the control of glycogen metabolism and highlight altered glycogen accumulation as a key contributor to neurodegeneration in LD.


La Enfermedad de Lafora (LD) es una epilepsia progresiva fatal. Al principio del siglo XX, la presencia de inclusiones de glucógeno anormal (después llamadas Cuerpos de Lafora, LBs) en las neuronas de los pacientes ya se describía como su rasgo distintivo. Sin embargo, el mecanismo de formación de ese glucógeno anormal en LD es aún motivo de discusión así como la relación entre la formación de LBs y la degeneración de las neuronas que los presentan. Nosotros afrontamos estas cuestiones mediante la generación y el estudio de un ratón modelo de la enfermedad, el knockout del gen Malina. En nuestro trabajo se demuestra por primera vez la presencia de LBs en astrocitos (el tipo celular donde normalmente se acumula el glucógeno en el cerebro). Destacamos la alta susceptibilidad de las neuronas (que normalmente no acumulan glucógeno) a la muerte celular inducida por acumulación del polisacárido. Finalmente, concluimos que los genes mutados responsables de LD tienen un papel crucial en la acumulación del glucógeno y la regulación de la Glucógeno Sintasa, el único enzima capaz de sintetizarlo. Por este motivo proponemos la GS como potencial diana para el tratamiento de la LD.

Foto grupo octubre

El grupo dirigido por el profesor Guinovart desarrolla proyectos sobre el metabolismo del glucógeno y sus disfunciones en la diabetes y en diversas enfermedades neurodegenerativas como la enfermedad de Lafora. Los estudios sobre el metabolismo del glucógeno han permitido identificar un gran número de enzimas y metabolitos intermediarios que participan en la síntesis y degradación de este polisacárido. Sin embargo, constantemente se descubren nuevos factores y procesos que forman parte de regulación, síntesis y degradación del glucógeno. Además, los datos sobre los mecanismos de control en órganos diferentes y en condiciones fisiológicas diversas son incompletos. La alteración de uno de estos mecanismos podría dar lugar a serias patologías como la diabetes y la enfermedad de Lafora. El descubrimiento de compuestos que neutralizan las alteraciones del metabolismo de la glucosa tiene un interés potencial para el tratamiento de la diabetes mellitus y de enfermedades neurodegenerativas com la de Lafora.

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