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

Abstract

Amyotrophic lateral sclerosis is a progres- (5) to propose that it is a dearth of activity that leads to the neurodegenerative syndrome.Studies of humans with ALS are complicated by the lack of genetic homogeneity or environmental uniformity. Moreover, possible early signs of disease that might appear prior to overt symptoms and could allow preemptive medical intervention are difficult to identify. For these reasons, it is highly desirable to develop an animal model of FALS. The transgenic mouse system (6-8) is well suited to development of such an animal model. Genes introduced into the mouse germ line are often efficiently expressed (9) and can act in a dominant manner to cause diseases that closely resemble the human disorder with respect to phenotype and underlying pathogenetic mechanism (10-12).We have exploited this system to study the role of altered SOD-1 expression in the pathogenesis of ALS and to attempt to develop an animal model of the disease. We introduced a missense mutation, Gly-86 -> Arg, into the fourth exon of a 15-kb mouse genomic clone that we had isolated (13). The same mutation has been observed in the corresponding amino acid residue (position 85) of some patients with FALS (4, 5).In two lines of mice that produced high levels of transgene mRNA in the central nervous system, motor paralysis developed and was associated with degenerative changes of motoneurons within the spinal cord, brain stem, and neocortex. Biochemical measurements of SOD activity in these animals did not reveal a diminution of activity. These findings establish that altered SOD-1 expression can cause motoneuron degeneration and that this degeneration is not associated with reduced SOD activity. Further, these animals constitute a potentially valuable animal model of ALS.

Resveratrol Improves Motoneuron Function and Extends Survival in SOD1G93A ALS Mice

“…This model recapitulates most relevant clinical and histopathological features of both familial and sporadic forms of the human disease [3]. It is also of relevance that alterations of the SOD1 protein have been reported in sporadic ALS patients [4], increasing the interest of this murine model.…”

“…expresses the human mutated form of the SOD1 gene with a glycine to alanine conversion at the 93rd codon [3]. This model recapitulates most relevant clinical and histopathological features of both familial and sporadic forms of the human disease [3].…”

Sigma-1R Agonist Improves Motor Function and Motoneuron Survival in ALS Mice

“…Based on these genetic mutations, transgenic animal models have been developed for the study of ALS. The most widely used model is a transgenic mouse with a glycine-to-alanine conversion at the 93rd codon of the SOD1 gene in high copy number (SOD1 G93A ) [3]. The phenotype of this mice recapitulates several clinical and histopathological features of both familial and sporadic forms of the human disease [3].…”

“…The most widely used model is a transgenic mouse with a glycine-to-alanine conversion at the 93rd codon of the SOD1 gene in high copy number (SOD1 G93A ) [3]. The phenotype of this mice recapitulates several clinical and histopathological features of both familial and sporadic forms of the human disease [3]. Moreover, it has been recently reported that alterations of the SOD1 protein are also related to sporadic ALS cases [4], increasing the interest in the study of transgenic animals.…”

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

“…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.…”