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

G. D. Ghadge, J. P. Lee, V. P. Bindokas, J. Jordan, L. Ma, R. J. Miller, R. P. Roos*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

182 Scopus citations

Abstract

Mutations in human Cu/Zn superoxide dismutase-1 (SOD) cause ~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.

Original languageEnglish (US)
Pages (from-to)8756-8766
Number of pages11
JournalJournal of Neuroscience
Volume17
Issue number22
DOIs
StatePublished - 1997

Keywords

  • Apoptosis
  • Familial amyotrophic lateral sclerosis
  • Neurodegeneration
  • Oxidative stress
  • Recombinant adenovirus
  • Superoxide dismutase- 1

ASJC Scopus subject areas

  • Neuroscience(all)

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