title: Neurodegeneration and functional impairments associated with glycogen synthase accumulation in a mouse model of Lafora disease.
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.
authors: Institute for Research in Biomedicine (IRB Barcelona) Barcelona, Spain.
authors: Jordi
authors: J
authors: Valles-Ortega
authors: Jordi
authors: J
authors: Duran
authors: Mar
authors: M
authors: Garcia-Rocha
authors: Carles
authors: C
authors: Bosch
authors: Isabel
authors: I
authors: Saez
authors: Lluís
authors: L
authors: Pujadas
authors: Anna
authors: A
authors: Serafin
authors: Xavier
authors: X
authors: Cañas
authors: Eduardo
authors: E
authors: Soriano
authors: José M
authors: JM
authors: Delgado-García
authors: Agnès
authors: A
authors: Gruart
authors: Joan J
authors: JJ
authors: Guinovart
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000201:enzymology; D004195:Disease Models, Animal; D005260:Female; D006003:Glycogen / Q000378:metabolism; D006006:Glycogen Synthase / Q000235:genetics / Q000378:metabolism*; D006624:Hippocampus / Q000201:enzymology; D006801:Humans; D002479:Inclusion Bodies / Q000201:enzymology / Q000235:genetics; D020192:Lafora Disease / Q000201:enzymology* / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009410:Nerve Degeneration / Q000201:enzymology* / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D009474:Neurons / Q000201:enzymology
chemical_list: D006003:Glycogen; D006006:Glycogen Synthase