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Glycogen metabolism in tissues from a mouse model of Lafora disease
Wei Wang1, Hannes Lohi, Alexander V Skurat
1Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202-5122, USA.
Abstract:
Laforin, encoded by the EPM2A gene, by sequence is a member of the dual specificity protein phosphatase family. Mutations in the EPM2A gene account for around half of the cases of Lafora disease, an autosomal recessive neurodegenerative disorder, characterized by progressive myoclonus epilepsy. The hallmark of the disease is the presence of Lafora bodies, which contain polyglucosan, a poorly branched form of glycogen, in neurons, muscle and other tissues. Glycogen metabolizing enzymes were analyzed in a transgenic mouse over-expressing a dominant negative form of laforin that accumulates Lafora bodies in several tissues. Skeletal muscle glycogen was increased 2-fold as was the total glycogen synthase protein. However, the -/+glucose-6-P activity of glycogen synthase was decreased from 0.29 to 0.16. Branching enzyme activity was increased by 30%. Glycogen phosphorylase activity was unchanged. In whole brain, no differences in glycogen synthase or branching enzyme activities were found. Although there were significant differences in enzyme activities in muscle, the results do not support the hypothesis that Lafora body formation is caused by a major change in the balance between glycogen elongation and branching activities.
Insights
Laforin deficiency causes Lafora disease, characterized by abnormal glycogen (polyglucosan) accumulation. This study found altered glycogen metabolism in muscle but not brain, suggesting complex disease mechanisms beyond simple enzyme imbalances.
Area of Science:
- Biochemistry
- Neuroscience
- Genetics
Background:
- Laforin, a dual specificity protein phosphatase encoded by the EPM2A gene, is implicated in Lafora disease.
- Lafora disease is an autosomal recessive neurodegenerative disorder marked by progressive myoclonus epilepsy and Lafora bodies (polyglucans).
- Mutations in EPM2A cause approximately half of Lafora disease cases.
Purpose of the Study:
- To investigate the role of glycogen metabolizing enzymes in Lafora body formation.
- To analyze glycogen metabolism in a transgenic mouse model overexpressing a dominant-negative laforin.
Main Methods:
- Analysis of glycogen metabolizing enzymes (glycogen synthase, branching enzyme, glycogen phosphorylase) in skeletal muscle and whole brain.
- Comparison between wild-type and transgenic mice overexpressing a dominant-negative laforin.
Main Results:
- Skeletal muscle showed a 2-fold increase in glycogen and total glycogen synthase protein.
- Glycogen synthase activity decreased, while branching enzyme activity increased by 30% in skeletal muscle.
- No significant differences in glycogen synthase or branching enzyme activities were observed in the whole brain.
Conclusions:
- Altered glycogen metabolism in skeletal muscle does not fully explain Lafora body formation.
- The results do not support a hypothesis that Lafora body formation is caused by a major imbalance between glycogen elongation and branching activities.
- Disease mechanisms may involve more complex interactions or factors beyond the analyzed enzyme activities.
