Mechanism suppressing glycogen synthesis in neurons and its demise in progressive myoclonus epilepsy.
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.
Vilchez
David
D
Institute for Research in Biomedicine and University of Barcelona, Barcelona Science Park, Josep Samitier 1-5, E-08028 Barcelona, Spain.
Ros
Susana
S
Cifuentes
Daniel
D
Pujadas
Lluís
L
Vallès
Jordi
J
García-Fojeda
Belén
B
Criado-García
Olga
O
Fernández-Sánchez
Elena
E
Medraño-Fernández
Iria
I
Domínguez
Jorge
J
García-Rocha
Mar
M
Soriano
Eduardo
E
Rodríguez de Córdoba
Santiago
S
Guinovart
Joan J
JJ
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D001253:Astrocytes / Q000502:physiology; D002352:Carrier Proteins / Q000494:pharmacology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D004622:Embryo, Mammalian; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006003:Glycogen / Q000378:metabolism*; D024981:Glycogen Phosphorylase / Q000378:metabolism; D006006:Glycogen Synthase / Q000378:metabolism; D006801:Humans; D020287:In Situ Nick-End Labeling / Q000379:methods; D051379:Mice; D009154:Mutation / Q000502:physiology; D009474:Neurons / Q000378:metabolism*; D054558:Protein Tyrosine Phosphatases, Non-Receptor / Q000494:pharmacology; D034622:RNA Interference / Q000502:physiology; D014162:Transfection; D014404:Tubulin / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases
D002352:Carrier Proteins; D005904:Glial Fibrillary Acidic Protein; D014404:Tubulin; C462941:beta3 tubulin, mouse; D006003:Glycogen; C478960:NHLRC1 protein, human; D044767:Ubiquitin-Protein Ligases; D024981:Glycogen Phosphorylase; D006006:Glycogen Synthase; D054558:Protein Tyrosine Phosphatases, Non-Receptor; C114990:EPM2A protein, human