Expression of N19S-SOD1, an SOD1 mutant found in sporadic amyotrophic lateral sclerosis patients, induces low-grade motoneuronal toxicity

J Neurosci Res. 2005 Sep 1;81(5):720-9. doi: 10.1002/jnr.20594.


Amyotrophic lateral sclerosis (ALS) is the most common fatal motor neuron disease. It has been generally accepted that the proapoptotic property of the familial ALS (FALS)-linked mutant SOD1 genes plays an important role in the pathogenesis of some FALS cases. We found here that expression of N19S-SOD1, a novel SOD1 mutant originally found in a sporadic ALS patient, induces lower grade death in NSC34 cells than FALS-linked mutant SOD1. In agreement, intracytoplasmic aggregate formation and SOD1 polymerization are less prominently induced by ectopic expression of N19S-SOD1 than FALS-linked mutant SOD1. We further found that additional cell stresses, such as inhibition of proteasomal activity or up-regulation of intracellular oxidative stress, enhance N19S-SOD1-induced aggregate formation and polymerization of N19S-SOD1. Such analysis of the intracellular polymerization and the ubiquitination of N19S-SOD1 have further suggested that it is recognized as a misfolded protein, like FALS-linked mutant SOD1, whereas wild-type SOD1 is not. Altogether, it is speculated that the N19S mutation of SOD1 in cooperation with associated cell stresses contributes to the onset of ALS as a risk factor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyotrophic Lateral Sclerosis / genetics*
  • Amyotrophic Lateral Sclerosis / pathology
  • Animals
  • CHO Cells
  • Cell Death / physiology
  • Cricetinae
  • Humans
  • Immunoblotting
  • Mice
  • Motor Neurons / pathology*
  • Mutation
  • Oxidative Stress
  • Superoxide Dismutase / genetics
  • Superoxide Dismutase / metabolism*
  • Superoxide Dismutase-1
  • Transfection


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