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Neurodegeneration and functional impairments associated with glycogen synthase accumulation in a mouse model of Lafora disease

Reference: EMBO Mol Med. 2011 Aug 29. doi: 10.1002/emmm.201100174.
Authors: 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
Summary:
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.
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REFERENCIA DEL GRUPO E INVESTIGADOR
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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