Transgenic mice expressing an altered murine superoxide dismutase gene provide an animal model of amyotrophic lateral sclerosis

Michael E. Ripps, George W. Huntley, Patrick R. Hof, John Morrison, Jon W. Gordon

Research output: Contribution to journalArticlepeer-review

584 Scopus citations

Abstract

Amyotrophic lateral sclerosis is a progressive neurodegenerative disorder primarily involving motoneurons. A subset of individuals with familial autosomal dominant forms of the disease have mutations of the copper/zinc superoxide dismutase (Cu/Zn SOD, SOD-1) gene, which encodes a ubiquitously expressed enzyme that plays a key role in oxygen free radical scavenging. This observation suggests that altered or reduced SOD-1 activity may play a role in the neurodegenerative process. To explore this possibility further, we have introduced a mutation into the mouse SOD-1 gene that corresponds to one of the changes found in the human gene in familial amyotrophic lateral sclerosis. Integration and expression of this mouse gene in transgenic mice was identified by the presence of a unique restriction enzyme site in the transgene coding sequence generated by introduction of the mutation. We report here that high expression of this altered gene in the central nervous systems of transgenic mice is associated with an age-related rapidly progressive decline of motor function accompanied by degenerative changes of motoneurons within the spinal cord, brain stem, and neocortex. These findings indicate a causative relationship between altered SOD activity and motoneuron degeneration. Moreover, biochemical studies indicate normal levels of total SOD activity in transgenic mouse tissues, results that indicate that the neurodegenerative disorder does not result from a diminution of activity and, as such, represents a dominant 'gain of function' mutation.

Original languageEnglish (US)
Pages (from-to)689-693
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume92
Issue number3
DOIs
StatePublished - Jan 31 1995
Externally publishedYes

Keywords

  • age-related disease
  • free radicals
  • motoneuron degeneration

ASJC Scopus subject areas

  • General

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