Motor Neuron Degeneration in Mice that Express a Human Cu,Zn Superoxide Dismutase Mutation

Abstract

Mutations of human Cu,Zn superoxide dismutase (SOD) are found in about 20 percent of patients with familial amyotrophic lateral sclerosis (ALS). Expression of high levels of human SOD containing a substitution of glycine to alanine at position 93--a change that has little effect on enzyme activity--caused motor neuron disease in transgenic mice. The mice became paralyzed in one or more limbs as a result of motor neuron loss from the spinal cord and died by 5 to 6 months of age. The results show that dominant, gain-of-function mutations in SOD contribute to the pathogenesis of familial ALS.

Novel harmful effects of [60]fullerene on mouse embryos in vitro and in vivo

“…Hydrogen peroxide and hydroxy radicals have been implicated in neuronal degeneration induced by monoamine neurotoxins such as 6-hydroxydopamine or 5,7-dihydroxytryptamine. Recently, Gurney et al [11] reported that the transgenic mice that express wild-type or mutant forms of human SOD were produced and that mice expressing wild-type human SOD show no signs of neuron disease, but the transgenic mice expressing the largest amounts of mutant SOD in the brain caused motor neuron disease. These and our present results indicate that the neurons of embryos are sensitive to active oxygen species at the developmental stage.…”

Ablation of de novo DNA methyltransferase Dnmt3a in the nervous system leads to neuromuscular defects and shortened lifespan

“…The impaired survival and motor defects in Dnmt3a/Nes-Cre1 mutant mice are reminiscent of those seen in SOD1 (superoxide dismutase) transgenics, a model for amyotrophic lateral sclerosis (Gurney, 1994;Gurney et al, 1994;Weydt et al, 2003;Lalonde et al, 2005). SOD1 transgenic mice develop motor neuron disease and lose innervation of muscle fibers , though these symptoms are more severe than those seen in Dnmt3a/Nes-Cre1 mutant mice.…”

Bcl-2 expression by retrograde transport of adenoviral vectors with Cre-loxP recombination system in motor neurons of mutant SOD1 transgenic mice

“…Transgenic mice carrying a high copy number of a mutant allele human SOD1 (G93A) gene [B6SJL-TgN (SOD1-G93A)1Gur] 4 and their wild-type non-transgenic littermates (B6SJL) were purchased from the Jackson Laboratory (Bar Harbor, ME, USA), and housed under an atmosphere free of known pathogens. Selective breeding maintained the mutant SOD1 (G93A) transgene in the hemizygous state in B6SJLF1 hybrids.…”

“…The line of SOD1 transgenic mice containing an amino acid substitution of glycine at position 93 by alanine (G93A) has been reported to become paralyzed in one or more limbs due to loss of motor neurons from the spinal cord, with these mice dying by 4 to 5 months of age. 4,5 Pathologic changes with vacuolar formation in the anterior horns of the spinal cord and in selected brainstem nuclei have been seen as early as less than 3 month at a pre-clinical stage. 6 Although the mechanisms by which ALS leads to motor neuron degeneration remain unclear, they are suggested to be associated with a deficiency of neurotrophic factors, excessive excitatory amino acids, excessive oxidative stress, and promoted apoptosis.…”