RT Journal Article
T1 Mechanism suppressing glycogen synthesis in neurons and its demise in progressive myoclonus epilepsy
A1 Vilchez, David
A1 Ros, Susana
A1 Cifuentes, Daniel
A1 Pujadas, Lluís
A1 Vallès, Jordi
A1 García-Fojeda García-Valdecasas, María Belén
A1 Criado-García, Olga
A1 Fernández-Sánchez, Elena
A1 Medraño-Fernández, Iria
A1 Domínguez, Jorge
A1 García-Rocha, Mar
A1 Soriano, Eduardo
A1 Rodríguez de Córdoba, Santiago
A1 Guinovart, Joan
AB 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.
PB Springer Nature
SN 1097-6256
YR 2007
FD 2007
LK https://hdl.handle.net/20.500.14352/98244
UL https://hdl.handle.net/20.500.14352/98244
LA eng
NO 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
NO Ministerio de Educación y Ciencia (España)
NO Instituto de Salud Carlos III
NO Fundació La Caixa
NO Fundació La Marató de TV3
NO Fundación Marcelino Botín
DS Docta Complutense
RD 11 ago 2024