Human Molecular Genetics Advance Access published online on August 22, 2005
Human Molecular Genetics, doi:10.1093/hmg/ddi306
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1 Program in Genetics and Genomic Biology, The Hospital for Sick Children, Toronto M5G 1X8, Canada
* To whom correspondence should be addressed. Lafora progressive myoclonus epilepsy, caused by defective laforin or malin, presents insidiously in normal teenagers with cognitive decline, followed by rapidly intractable epilepsy, dementia and death. Pathology reveals neurodegeneration with neurofibrillary tangle formation and Lafora bodies (LB). LB are deposits of starch-like polyglucosans, insufficiently branched and hence insoluble glycogen molecules resulting from glycogen synthase (GS) overactivity relative to glycogen branching enzyme activity. We previously made the unexpected observation that laforin, in the absence of which polyglucosans accumulate, specifically binds polyglucosans. This suggested that laforin's role is to detect polyglucosan appearances during glycogen synthesis and initiate mechanisms to downregulate GS. Glycogen synthase kinase 3 (GSK3) is the principal inhibitor of GS. Dephosphorylation of GSK3 at Ser 9 activates GSK3 to inhibit GS through phosphorylation at multiple sites. Glucose 6-phosphate is a potent allosteric activator of GS. At times of glucose plenty, its levels are high, and its activation of GS overrides any phospho-inhibition. Here we show that laforin is a GSK3 Ser 9 phosphatase, and therefore capable of inactivating GS through GSK3. We also show that laforin interacts with malin, and that malin is an E3 ubiquitin ligase that binds GS. We propose that laforin, in response to appearance of polyglucosans, directs two negative feedback pathways, one, polyglucosan-laforin-GSK3-GS, to inhibit GS activity, and the other, polyglucosan-laforin-malin-GS to remove GS through proteasomal degradation.
Received June 12, 2005
Revised August 5, 2005
Accepted August 5, 2005
Article
Novel glycogen synthase kinase 3 (GSK3) and ubiquitination pathways in progressive myoclonus epilepsy
2 Department of Pathology and Laboratory Medicine, The Hospital for Sick Children, Toronto, M5G 1X8, Canada
3 Program in Genetics and Genomic Biology and Department of Paediatrics (Neurology), The Hospital for Sick Children, Toronto M5G 1X8, Canada
Berge A. Minassian, E-mail: bminass{at}sickkids.ca
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