Vilchez, DavidRos, SusanaCifuentes, DanielPujadas, LluísVallès, JordiGarcía-Fojeda García-Valdecasas, María BelénCriado-García, OlgaFernández-Sánchez, ElenaMedraño-Fernández, IriaDomínguez, JorgeGarcía-Rocha, MarSoriano, EduardoRodríguez de Córdoba, SantiagoGuinovart, Joan2024-02-022024-02-022007Vilchez, D., Ros, S., Cifuentes, D. et al. Mechanism suppressing glycogen synthesis in neurons and its demise in progressive myoclonus epilepsy. Nat Neurosci 10, 1407–1413 (2007). https://doi.org/10.1038/nn19981097-625610.1038/nn1998https://hdl.handle.net/20.500.14352/98244Glycogen 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.engAttribution 4.0 Internationaljournal article1546-1726https://doi.org/10.1038/nn1998https://pubmed.ncbi.nlm.nih.gov/17952067/metadata only access577.1577.2575612.8GlycogenNeuronsLafora diseaseGlycogen synthaseLaforinMalinProtein targeting to glycogenProtein phosphatase 1Proteasome-dependent degradationBioquímica (Biología)Biología molecular (Biología)Neurociencias (Biológicas)Genética2403 Bioquímica2415 Biología Molecular2409 Genética2407.01 Cultivo Celular