Novel glycogen synthase kinase 3 and ubiquitination pathways in progressive myoclonus epilepsy

Lafora progressive myoclonus epilepsy, caused by defective laforinor malin, insidiously present in normal teenagers with cognitivedecline, followed by rapidly intractable epilepsy, dementiaand death. Pathology reveals neurodegeneration with neurofibrillarytangle formation and Lafora bodies (LBs). LBs are deposits ofstarch-like polyglucosans, insufficiently branched and henceinsoluble 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, specificallybinds polyglucosans. This suggested that laforin's role is todetect polyglucosan appearances during glycogen synthesis andto initiate mechanisms to downregulate GS. Glycogen synthasekinase 3 (GSK3) is the principal inhibitor of GS. Dephosphorylationof GSK3 at Ser 9 activates GSK3 to inhibit GS through phosphorylationat multiple sites. Glucose-6-phosphate is a potent allostericactivator of GS. Glucose-6-phosphate levels are high when theamount of glucose increases and its activation of GS overridesany phospho-inhibition. Here, we show that laforin is a GSK3Ser 9 phosphatase, and therefore capable of inactivating GSthrough GSK3. We also show that laforin interacts with malinand that malin is an E3 ubiquitin ligase that binds GS. We proposethat laforin, in response to appearance of polyglucosans, directstwo negative feedback pathways: polyglucosan–laforin–GSK3–GSto inhibit GS activity and polyglucosan–laforin–malin–GSto remove GS through proteasomal degradation.