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EMBO Mol Med. 2011 Nov;3(11):667-81. doi: 10.1002/emmm.201100174. Epub 2011 Aug 29.

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

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1
Institute for Research in Biomedicine (IRB Barcelona) Barcelona, Spain.

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.

PMID:
21882344
PMCID:
PMC3377110
DOI:
10.1002/emmm.201100174
[Indexed for MEDLINE]
Free PMC Article
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