Glycogen synthesis is normally absent in neurons. However, inclusion bodies resembling abnormal glycogen accumulate in several neurological diseases, particularly in progressive myoclonus epilepsy or Lafora disease. We show here that mouse neurons have the enzymatic machinery for synthesizing glycogen, but that it is suppressed by retention of muscle glycogen synthase (MGS) in the phosphorylated, inactive state. This suppression was further ensured by a complex of laforin and malin, which are the two proteins whose mutations cause Lafora disease. The laforin-malin complex caused proteasome-dependent degradation both of the adaptor protein targeting to glycogen, PTG, which brings protein phosphatase 1 to MGS for activation, and of MGS itself. Enforced expression of PTG led to glycogen deposition in neurons and caused apoptosis. Therefore, the malin-laforin complex ensures a blockade of neuronal glycogen synthesis even under intense glycogenic conditions. Here we explain the formation of polyglucosan inclusions in Lafora disease by demonstrating a crucial role for laforin and malin in glycogen synthesis.

Lafora progressive myoclonus epilepsy (LD) is a fatal autosomal recessive neurodegenerative disorder characterized by the presence of glycogen-like intracellular inclusions called Lafora bodies. LD is caused by mutations in two genes, EPM2A and EPM2B, encoding respectively laforin, a dual-specificity protein phosphatase, and malin, an E3 ubiquitin ligase. Previously, we and others have suggested that the interactions between laforin and PTG (a regulatory subunit of type 1 protein phosphatase) and between laforin and malin are critical in the pathogenesis of LD. Here, we show that the laforin-malin complex downregulates PTG-induced glycogen synthesis in FTO2B hepatoma cells through a mechanism involving ubiquitination and degradation of PTG. Furthermore, we demonstrate that the interaction between laforin and malin is a regulated process that is modulated by the AMP-activated protein kinase (AMPK). These findings provide further insights into the critical role of the laforin-malin complex in the control of glycogen metabolism and unravel a novel link between the energy sensor AMPK and glycogen metabolism. These data advance our understanding of the functional role of laforin and malin, which hopefully will facilitate the development of appropriate LD therapies.