Laforin, the most common protein mutated in Lafora disease, regulates autophagy

Hum Mol Genet. 2010 Jul 15;19(14):2867-76. doi: 10.1093/hmg/ddq190. Epub 2010 May 7.

Abstract

Lafora disease (LD) is an autosomal recessive, progressive myoclonus epilepsy, which is characterized by the accumulation of polyglucosan inclusion bodies, called Lafora bodies, in the cytoplasm of cells in the central nervous system and in many other organs. However, it is unclear at the moment whether Lafora bodies are the cause of the disease, or whether they are secondary consequences of a primary metabolic alteration. Here we describe that the major genetic lesion that causes LD, loss-of-function of the protein laforin, impairs autophagy. This phenomenon is confirmed in cell lines from human patients, mouse embryonic fibroblasts from laforin knockout mice and in tissues from such mice. Conversely, laforin expression stimulates autophagy. Laforin regulates autophagy via the mammalian target of rapamycin kinase-dependent pathway. The changes in autophagy mediated by laforin regulate the accumulation of diverse autophagy substrates and would be predicted to impact on the Lafora body accumulation and the cell stress seen in this disease that may eventually contribute to cell death.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autophagy / genetics*
  • COS Cells
  • Cells, Cultured
  • Chlorocebus aethiops
  • Humans
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Intracellular Signaling Peptides and Proteins / physiology
  • Lafora Disease / genetics*
  • Lafora Disease / pathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mutant Proteins / genetics
  • Mutant Proteins / physiology
  • Phagosomes / genetics
  • Phagosomes / metabolism
  • Protein Processing, Post-Translational / genetics
  • Protein Tyrosine Phosphatases, Non-Receptor / genetics*
  • Protein Tyrosine Phosphatases, Non-Receptor / physiology*
  • Protein-Serine-Threonine Kinases / metabolism
  • Protein-Serine-Threonine Kinases / physiology
  • Signal Transduction / genetics
  • Signal Transduction / physiology
  • TOR Serine-Threonine Kinases

Substances

  • Intracellular Signaling Peptides and Proteins
  • Mutant Proteins
  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • mTOR protein, mouse
  • Protein-Serine-Threonine Kinases
  • Protein Tyrosine Phosphatases, Non-Receptor
  • EPM2A protein, human