Absence of lipofuscin in motor neurons of SOD1-linked ALS mice

Proc Natl Acad Sci U S A. 2014 Jul 29;111(30):11055-60. doi: 10.1073/pnas.1409314111. Epub 2014 Jul 14.

Abstract

Lipofuscin, or aging pigment, is accreted as red autofluorescence in the lysosomes of motor neuron cell bodies in the ventral horn of WT mice by 3 mo of age. Strikingly, in two presymptomatic ALS mouse strains transgenic for mutant human Cu/Zn superoxide dismutase (SOD1), G85R SOD1YFP and G93A SOD1, little or no lipofuscin was detected in motor neuron cell bodies. Two markers of autophagy, sequestosome 1 (SQSTM1/p62) and microtubule-associated protein 1 light chain 3 (LC3), were examined in the motor neuron cell bodies of G85R SOD1YFP mice and found to be reduced relative to WT SOD1YFP transgenic mice. To elucidate whether the autophagy/lysosome pathway was either impaired or hyperactive in motor neurons, chloroquine was administered to 3-mo-old G85R SOD1YFP mice to block lysosomal hydrolysis. After 2 wk, lipofuscin was now observed in motor neurons, and SQSTM1 and LC3 levels approached those of WT SOD1YFP mice, suggesting that the autophagy/lysosome pathway is hyperactive in motor neurons of SOD1-linked ALS mice. This seems to be mediated at least in part through the mammalian target of rapamycin complex 1 (MTORC1) pathway, because levels of Ser757-phosphorylated Unc-51-like kinase 1 (ULK1), an MTORC1 target, were greatly reduced in the G85R SOD1YFP motor neurons, correspondent to an activated state of ULK1 that initiates autophagy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism
  • Amino Acid Substitution
  • Amyotrophic Lateral Sclerosis / genetics
  • Amyotrophic Lateral Sclerosis / metabolism*
  • Amyotrophic Lateral Sclerosis / pathology
  • Animals
  • Autophagy*
  • Autophagy-Related Protein-1 Homolog
  • Heat-Shock Proteins / genetics
  • Heat-Shock Proteins / metabolism
  • Humans
  • Lipofuscin / genetics
  • Lipofuscin / metabolism*
  • Lysosomes / genetics
  • Lysosomes / metabolism*
  • Lysosomes / pathology
  • Mechanistic Target of Rapamycin Complex 1
  • Mice
  • Mice, Transgenic
  • Microtubule-Associated Proteins / genetics
  • Microtubule-Associated Proteins / metabolism
  • Motor Neurons / metabolism*
  • Motor Neurons / pathology
  • Multiprotein Complexes / genetics
  • Multiprotein Complexes / metabolism
  • Mutation, Missense
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / metabolism
  • Sequestosome-1 Protein
  • Superoxide Dismutase / genetics
  • Superoxide Dismutase / metabolism*
  • Superoxide Dismutase-1
  • TOR Serine-Threonine Kinases / genetics
  • TOR Serine-Threonine Kinases / metabolism

Substances

  • Adaptor Proteins, Signal Transducing
  • Heat-Shock Proteins
  • Lipofuscin
  • Map1lc3b protein, mouse
  • Microtubule-Associated Proteins
  • Multiprotein Complexes
  • SOD1 protein, human
  • Sequestosome-1 Protein
  • Sqstm1 protein, mouse
  • Sod1 protein, mouse
  • Superoxide Dismutase
  • Superoxide Dismutase-1
  • Autophagy-Related Protein-1 Homolog
  • Mechanistic Target of Rapamycin Complex 1
  • Protein Serine-Threonine Kinases
  • TOR Serine-Threonine Kinases
  • Ulk1 protein, mouse