Glycogen accumulation underlies neurodegeneration and autophagy impairment in Lafora disease

Hum Mol Genet. 2014 Jun 15;23(12):3147-56. doi: 10.1093/hmg/ddu024. Epub 2014 Jan 22.

Abstract

Lafora disease is a fatal neurodegenerative condition characterized by the accumulation of abnormal glycogen inclusions known as Lafora bodies. It is an autosomal recessive disorder caused by mutations in either the laforin or malin gene. To study whether glycogen is primarily responsible for the neurodegeneration in Lafora disease, we generated malin knockout mice with impaired (totally or partially) glycogen synthesis. These animals did not show the increase in markers of neurodegeneration, the impairments in electrophysiological properties of hippocampal synapses, nor the susceptibility to kainate-induced epilepsy seen in the malin knockout model. Interestingly, the autophagy impairment that has been described in malin knockout animals was also rescued in this double knockout model. Conversely, two other mouse models in which glycogen is over-accumulated in the brain independently of the lack of malin showed impairment in autophagy. Our findings reveal that glycogen accumulation accounts for the neurodegeneration and functional consequences seen in the malin knockout model, as well as the impaired autophagy. These results identify the regulation of glycogen synthesis as a key target for the treatment of Lafora disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autophagy*
  • Biomarkers / metabolism
  • Disease Models, Animal
  • Dual-Specificity Phosphatases / metabolism*
  • Electrical Synapses / metabolism
  • Epilepsy / chemically induced
  • Epilepsy / pathology
  • Glycogen / metabolism*
  • Glycogen Synthase / genetics*
  • Glycogen Synthase / metabolism
  • Hippocampus / physiology
  • Humans
  • Inclusion Bodies / genetics
  • Inclusion Bodies / metabolism
  • Kainic Acid / pharmacology
  • Lafora Disease / metabolism
  • Lafora Disease / pathology
  • Lafora Disease / physiopathology*
  • Mice
  • Mice, Knockout
  • Mutation
  • Protein Tyrosine Phosphatases, Non-Receptor
  • Ubiquitin-Protein Ligases / genetics*
  • Ubiquitin-Protein Ligases / metabolism

Substances

  • Biomarkers
  • Glycogen
  • NHLRC1 protein, mouse
  • Ubiquitin-Protein Ligases
  • Glycogen Synthase
  • Dual-Specificity Phosphatases
  • Epm2a protein, mouse
  • Protein Tyrosine Phosphatases, Non-Receptor
  • Kainic Acid