Human Molecular Genetics Advance Access originally published online on August 22, 2005
Human Molecular Genetics 2005 14(18):2727-2736; doi:10.1093/hmg/ddi306
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Novel glycogen synthase kinase 3 and ubiquitination pathways in progressive myoclonus epilepsy
1Program in Genetics and Genomic Biology, 2Department of Pathology and Laboratory Medicine and 3Department of Paediatrics (Neurology), The Hospital for Sick Children, Toronto, Canada M5G 1X8
* To whom correspondence should be addressed. Tel: +1 4168136291; Fax: +1 4168136334; Email: bminass{at}sickkids.ca
Received June 12, 2005; Accepted August 5, 2005
Lafora progressive myoclonus epilepsy, caused by defective laforin or malin, insidiously present in normal teenagers with cognitive decline, followed by rapidly intractable epilepsy, dementia and death. Pathology reveals neurodegeneration with neurofibrillary tangle formation and Lafora bodies (LBs). LBs 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 to 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. Glucose-6-phosphate levels are high when the amount of glucose increases 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: polyglucosan–laforin–GSK3–GS to inhibit GS activity and polyglucosan–laforin–malin–GS to remove GS through proteasomal degradation.
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