Starch-like polyglucosan formation in neuronal dendrites in the Lafora form of human epilepsy: A theory of pathogenesis

Lafora disease is a teenage-onset fatal form of progressive myoclonus epilepsy. In this disease, starch-like polyglucosans are formed in neurons, specifically in the neuronal soma and dendrites. Laforin, the protein product of the disease gene, possesses a CBM20 type of starch-binding domain with which it preferentially binds starch over glycogen. It also contains a dual-specificity phosphatase domain with yet unknown phosphoprotein substrate(s). Since polyglucosans are abnormal in human cells and the probable cause of epilepsy in this disease, we theorize that laforin is designed to detect their appearance and initiate mechanisms to prevent their further formation or to promote their disposal. In this article, we review glycogen metabolism pertinent to neurons and the known pathology and biochemistry of Lafora disease and related rare human conditions with polyglucosan formation. We discuss the likeliest most direct pathways through which laforin may inhibit polyglucosan synthesis. We also discern the probable existence of a carbohydrate shuttle system to clear polyglucosans from dendrites. Finally, we detect that the phosphokinase glycogen synthase kinase 3 (GSK3) is a common thread in the pathways invoked to explain the role of laforin. We propose that GSK3 is likely an important participant in the control of polyglucosan formation and accumulation in human brain.