Rats expressing human cytosolic copper-zinc superoxide dismutase transgenes with amyotrophic lateral sclerosis: Associated mutations develop motor neuron disease

M. Nagai, M. Aoki, I. Miyoshi, M. Kato, P. Pasinelli, N. Kasai, Jr Brown, Y. Itoyama

Research output: Contribution to journalArticlepeer-review

274 Citations (Scopus)

Abstract

Some cases of familial amyotrophic lateral sclerosis (ALS) are caused by mutations in the gene encoding cytosolic, copperzinc superoxide dismutase (SOD1). We report here that rats that express a human SOD1 transgene with two different ALS-associated mutations (G93A and H46R) develop striking motor neuron degeneration and paralysis. As in the human disease and transgenic ALS mice, pathological analysis demonstrates selective loss of motor neurons in the spinal cords of these transgenic rats. In spinal cord tissues, this is accompanied by activation of apoptotic genes known to be activated by mutant SOD1 protein in vitro and in vivo. These animals provide additional support for the proposition that motor neuron death in SOD1-related ALS reflects one or more acquired, neurotoxic properties of the mutant SOD1 protein. The larger size of this rat model as compared with the ALS mice will facilitate studies involving manipulations of spinal fluid (implantation of intrathecal catheters for chronic therapeutic studies; CSF sampling) and spinal cord (e.g., direct administration of viral- and cellmediated therapies).

Original languageEnglish
Pages (from-to)9246-9254
Number of pages9
JournalJournal of Neuroscience
Volume21
Issue number23
DOIs
Publication statusPublished - 2001 Dec 1

Keywords

  • Caspase
  • Copper-zinc SOD
  • Familial amyotrophic lateral sclerosis
  • Glutamate
  • SOD1
  • Transgenic rats

ASJC Scopus subject areas

  • Neuroscience(all)

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