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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We thank J. Massagué for providing a critical review of the manuscript, P. Sanz and J.M. Serratosa for their advice, A. Adrover and E. Veza for their technical support, and T. Yates for correcting the manuscript. We also thank R.R. Gomis for the AdCMV-PTG virus, O. Baba for the monoclonal antibody to glycogen and D.G. Hardy for the gift of the PGSser7/10 antibody. This study was supported by grants from the Fundació La Caixa, Fundació La Marató de TV3, Fundación Marcelino Botín, the Spanish Ministry of Education and Science (SAF2005-00913; BFU2005-02253) and the Instituto de Salud Carlos III (CIBER-ER; RD06/0015/0030).
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Vilchez, 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/nn1998
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