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.

A study was conducted to form a unified hypothesis regarding the gonadotropin-related mechanisms that underlie alterations in the male reproductive system in individuals with diabetes. Streptozotocin-induced diabetes resulted in reduced fertility, prolificacy, and libido. Testes showed a marked decrease in the number and function of Leydig cells, the latter manifested as changes in the expression of biochemical markers, including the GLUT-3 hexose transporter, c-kit, insulin-like growth factor I (IGF-I), androgen receptors, and overall tyrosine phosphorylation, as assessed by Western blot and immunocytochemical analyses. The expression of c-kit, IGF-I, insulin, and follicle-stimulating hormone (FSH) receptors in the seminiferous tubules was also affected. Serum levels of luteinizing hormone (LH), FSH, and testosterone significantly decreased. There was a significant (P <.05) correlation between the serum levels of insulin and FSH. No significant correlation was found between the serum levels of insulin or glucose and LH. On the basis of our results, we conclude that, in insulin-dependent diabetes, 1) Leydig cell function and testosterone production decrease because of the absence of the stimulatory effect of insulin on these cells and an insulin-dependent decrease in FSH, which, in turn, reduces LH levels; and 2) sperm output and fertility are reduced because of a decrease in FSH caused by a reduction in insulin.

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.