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

Agnès Gruart,Isabel Saez,Carles Bosch,Anna Serafin,Xavier Cañas,Jordi Duran,Eduardo Soriano,Joan J. Guinovart,Mar Garcia‐Rocha,Jordi Valles‐Ortega,Lluís Pujadas,José M. Delgado‐García

doi:10.1002/emmm.201100174

Abstract

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.

Highlights

Lafora disease (LD) is caused by mutations in either the laforin or malin gene
We previously demonstrated that the laforin–malin complex blocks glycogen accumulation in cultured neurons by inducing the proteasome-dependent degradation of muscle glycogen synthase (MGS) and protein targeting to glycogen (PTG), a protein phosphatase-1 regulatory subunit responsible for the activation of MGS by dephosphorylation (Vilchez et al, 2007)
In the older mice, Lafora Bodies (LBs) were detected in regions of the brain that were unaffected at 4 months (Fig 1A)

Summary

INTRODUCTION

Glycogen is the principal storage form of glucose in animal and human cells It is mainly produced in the liver and muscles, and glycogen levels in the brain are low compared to these two tissues. Mutations in laforin would cause the overactivation of glycogen synthesis and increased phosphate content, which would alter glycogen structure, making it more prone to LB formation These hypotheses based only on the phosphatase activity of laforin fail to explain how malin deficiency causes LD. Laforin disruption in mice is described to cause neurodegeneration, myoclonus epilepsy and impaired behavioural response together with LB formation (Ganesh et al, 2002) and increased levels of MGS protein are found in the brain of this model (Tagliabracci et al, 2008). We report on the hippocampal functional impairment of the malin KO animals

RESULTS

DISCUSSION

MATERIALS AND METHODS