Mutant superoxide dismutase-1-linked familial amyotrophic lateral sclerosis: molecular mechanisms of neuronal death and protection

J Neurosci. 1997 Nov 15;17(22):8756-66. doi: 10.1523/JNEUROSCI.17-22-08756.1997.


Mutations in human Cu/Zn superoxide dismutase-1 (SOD) cause approximately 20% of cases of familial amyotrophic lateral sclerosis (FALS). We investigated the mechanism of mutant SOD-induced neuronal degeneration by expressing wild-type and mutant SODs in neuronal cells by means of infection with replication-deficient recombinant adenoviruses. Expression of two FALS-related mutant SODs (A4V and V148G) caused death of differentiated PC12 cells, superior cervical ganglion neurons, and hippocampal pyramidal neurons. Cell death included many features typical of apoptosis. Death could be prevented by copper (Cu2+) chelators, Bcl-2, glutathione, vitamin E, and inhibitors of caspases. Mutant SOD-expressing PC12 cells had higher rates of superoxide (O2-) production under a variety of conditions. The results support the hypothesis that mutant SOD induced-neurodegeneration is associated with disturbances of neuronal free radical homeostasis.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adenoviridae / genetics
  • Amyotrophic Lateral Sclerosis / enzymology*
  • Amyotrophic Lateral Sclerosis / genetics*
  • Animals
  • Antioxidants / pharmacology
  • Apoptosis / genetics
  • Cell Survival / physiology
  • Chelating Agents / pharmacology
  • Cricetinae
  • Family Health
  • Free Radicals / metabolism
  • Gene Expression Regulation, Enzymologic
  • Gene Expression Regulation, Viral
  • Humans
  • Kidney / cytology
  • Neurons / cytology*
  • Neurons / drug effects
  • Neurons / enzymology
  • Oxidative Stress / physiology
  • PC12 Cells
  • Rats
  • Recombinant Proteins / metabolism
  • Superoxide Dismutase / genetics*
  • Superoxides / metabolism
  • Transfection


  • Antioxidants
  • Chelating Agents
  • Free Radicals
  • Recombinant Proteins
  • Superoxides
  • Superoxide Dismutase