Tryptophan 32 potentiates aggregation and cytotoxicity of a copper/zinc superoxide dismutase mutant associated with familial amyotrophic lateral sclerosis

J Biol Chem. 2007 Jun 1;282(22):16329-35. doi: 10.1074/jbc.M610119200. Epub 2007 Mar 27.


One familial form of the neurodegenerative disease, amyotrophic lateral sclerosis, is caused by gain-of-function mutations in the gene encoding copper/zinc superoxide dismutase (SOD-1). This study provides in vivo evidence that normally occurring oxidative modification to SOD-1 promotes aggregation and toxicity of mutant proteins. The oxidation of Trp-32 was identified as a normal modification being present in both wild-type enzyme and SOD-1 with the disease-causing mutation, G93A, isolated from erythrocytes. Mutating Trp-32 to a residue with a slower rate of oxidative modification, phenylalanine, decreased both the cytotoxicity of mutant SOD-1 and its propensity to form cytoplasmic inclusions in motor neurons of dissociated mouse spinal cord cultures.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Substitution
  • Amyotrophic Lateral Sclerosis / genetics
  • Amyotrophic Lateral Sclerosis / metabolism*
  • Amyotrophic Lateral Sclerosis / pathology
  • Animals
  • Disease Models, Animal
  • Erythrocytes / enzymology
  • Erythrocytes / pathology
  • Humans
  • Inclusion Bodies / enzymology*
  • Inclusion Bodies / genetics
  • Inclusion Bodies / pathology
  • Mice
  • Mice, Transgenic
  • Motor Neurons / enzymology*
  • Motor Neurons / pathology
  • Mutation, Missense*
  • Oxidation-Reduction
  • Protein Processing, Post-Translational*
  • Rabbits
  • Spinal Cord / enzymology
  • Spinal Cord / pathology
  • Superoxide Dismutase / genetics
  • Superoxide Dismutase / metabolism*
  • Superoxide Dismutase-1
  • Tryptophan / genetics
  • Tryptophan / metabolism


  • SOD1 protein, human
  • Tryptophan
  • Sod1 protein, mouse
  • Superoxide Dismutase
  • Superoxide Dismutase-1