Open AccessNeurodegeneration and functional impairments associated with glycogen synthase accumulation in a mouse model of Lafora disease
Author(s) -
VallesOrtega Jordi,
Duran Jordi,
GarciaRocha Mar,
Bosch Carles,
Saez Isabel,
Pujadas Lluís,
Serafin Anna,
Cañas Xavier,
Soriano Eduardo,
DelgadoGarcía José M.,
Gruart Agnès,
Guinovart Joan J.
Publication year - 2011
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.1002/emmm.201100174
Subject(s) - lafora disease , neurodegeneration , hippocampal formation , biology , hippocampus , neuroscience , glycogen synthase , knockout mouse , glycogen , cerebellum , parvalbumin , endocrinology , microbiology and biotechnology , medicine , disease , gene , genetics , phosphatase , phosphorylation
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.