Coincident thresholds of mutant protein for paralytic disease and protein aggregation caused by restrictively expressed superoxide dismutase cDNA

Jiou Wang, Guilian Xu, Hilda H. Slunt, Victoria Gonzales, Michael Coonfield, David Fromholt, Neal G. Copeland, Nancy A. Jenkins, David R. Borchelt

Research output: Contribution to journalArticlepeer-review

Abstract

Familial amyotrophic lateral sclerosis (FALS) has been modeled in transgenic mice by introducing mutated versions of human genomic DNA encompassing the entire gene for Cu,Zn superoxide dismutase (SOD1). In this setting, the transgene is expressed throughout the body and results in mice that faithfully recapitulate many pathological and behavioral aspects of FALS. By contrast, transgenic mice made by introducing recombinant vectors, encoding cDNA genes, that target mutant SOD1 expression to motor neurons, only, or astrocytes, only, do not develop disease. Here, we report that mice transgenic for human SOD1 cDNA with the G37R mutation, driven by the mouse prion promoter, develop motor neuron disease. In this model, expression of the transgene is highest in CNS (both neurons and astrocytes) and muscle. The gene was not expressed in cells of the macrophage lineage. Although the highest expressing hemizygous transgenic mice fail to develop disease by 20 months of age, mice homozygous for the transgene show typical ALS-like phenotypes as early as 7 months of age. Spinal cords and brain stems from homozygous animals with motor neuron disease were found to contain aggregated species of mutant SOD1. The establishment of this SOD1-G37R cDNA transgenic model indicates that expression of mutant SOD1 proteins in the neuromuscular unit is sufficient to cause motor neuron disease. The expression levels required to induce disease coincide with the levels required to induce the formation of SOD1 aggregates.

Original languageEnglish (US)
Pages (from-to)943-952
Number of pages10
JournalNeurobiology of Disease
Volume20
Issue number3
DOIs
StatePublished - Dec 1 2005

Keywords

  • Disease model
  • FALS
  • Protein aggregation
  • Superoxide dismutase
  • Transgenic mice

ASJC Scopus subject areas

  • Neurology

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