| Summary: | Indiana University-Purdue University Indianapolis (IUPUI) === Glycogen, a branched polymer of glucose, serves as an osmotically
neutral means of storing glucose. Covalent phosphate is a trace component of
mammalian glycogen and has been a point of interest with respect to Lafora
disease, a fatal form of juvenile myoclonus epilepsy. Mutations in either the
EPM2A or EPM2B genes, which encode laforin and malin respectively, account
for ~90% of disease cases. A characteristic of Lafora disease is the formation of
Lafora bodies, which are mainly composed of an excess amount of abnormal
glycogen that is poorly branched and insoluble. Laforin-/- and malin-/- knockout
mice share several characteristics of the human disease, formation of Lafora
bodies in various tissues, increased glycogen phosphorylation and development
of neurological symptoms. The source of phosphate in glycogen has been an
area of interest and here we provide evidence that glycogen synthase is capable
of incorporating phosphate into glycogen. Mice lacking the glycogen targeting
subunit PTG of the PP1 protein phosphatase have decreased glycogen stores in
a number of tissues. When crossed with mice lacking either laforin or malin, the
double knockout mice no longer over-accumulate glycogen, Lafora body
formation is almost absent and the neurological disorders are normalized.
Another question has been whether the abnormal glycogen in the Lafora disease
mouse models can be metabolized. Using exercise to provoke glycogen
degradation, we show that in laforin-/- and malin-/- mice the insoluble, abnormal glycogen appears to be metabolically inactive. These studies suggest that a
therapeutic approach to Lafora disease may be to reduce the overall glycogen
levels in cells so that insoluble, metabolically inert pools of the polysaccharide do
not accumulate.
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