Article abstract


Nature Neuroscience 10, 1407 - 1413 (2007)
Published online: 21 October 2007 | doi:10.1038/nn1998

Mechanism suppressing glycogen synthesis in neurons and its demise in progressive myoclonus epilepsy

David Vilchez1, Susana Ros1, Daniel Cifuentes1, Lluís Pujadas1, Jordi Vallès1, Belén García-Fojeda2, Olga Criado-García2, Elena Fernández-Sánchez2, Iria Medraño-Fernández2, Jorge Domínguez1, Mar García-Rocha1, Eduardo Soriano1, Santiago Rodríguez de Córdoba2,3 & Joan J Guinovart1,3


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.

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  1. Institute for Research in Biomedicine and University of Barcelona, Barcelona Science Park, Josep Samitier 1-5, E-08028 Barcelona, Spain.
  2. Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, Ramiro de Maeztu 9, E-28040 Madrid, Spain.
  3. These authors contributed equally to this work.

Correspondence to: Santiago Rodríguez de Córdoba2,3 e-mail: SRdeCordoba@cib.csic.es

Correspondence to: Joan J Guinovart1,3 e-mail: guinovart@pcb.ub.es

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