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A Quick Phenotypic Neurological Scoring System for Evaluating Disease Progression in the SOD1-G93A Mouse Model of ALS
Published on: October 6, 2015
Expression of wild-type human superoxide dismutase-1 in mice causes amyotrophic lateral sclerosis
Karin S Graffmo1, Karin Forsberg, Johan Bergh
1Department of Medical Biosciences, Umeå University, SE-901 85 Umeå, Sweden.
Abstract:
A common cause of amyotrophic lateral sclerosis (ALS) is mutations in the gene encoding superoxide dismutase-1. There is evolving circumstantial evidence that the wild-type protein can also be neurotoxic and that it may more generally be involved in the pathogenesis of ALS. To test this proposition more directly, we generated mice that express wild-type human superoxide dismutase-1 at a rate close to that of mutant superoxide dismutase-1 in the commonly studied G93A transgenic model. These mice developed an ALS-like syndrome and became terminally ill after around 370 days. The loss of spinal ventral neurons was similar to that in the G93A and other mutant superoxide dismutase-1 models, and large amounts of aggregated superoxide dismutase-1 were found in spinal cords, but also in the brain. The findings show that wild-type human superoxide dismutase-1 has the ability to cause ALS in mice, and they support the hypothesis of a more general involvement of the protein in the disease in humans.
Insights
Wild-type superoxide dismutase-1 (SOD1) can cause amyotrophic lateral sclerosis (ALS) in mice. This finding suggests SOD1 may play a broader role in human ALS pathogenesis.
Area of Science:
- Neuroscience
- Genetics
- Molecular Biology
Background:
- Mutations in the superoxide dismutase-1 (SOD1) gene are a common cause of amyotrophic lateral sclerosis (ALS).
- Emerging evidence suggests that wild-type SOD1 protein may also contribute to neurotoxicity and ALS pathogenesis.
Purpose of the Study:
- To investigate whether wild-type human SOD1 can independently cause an ALS-like syndrome in mice.
- To directly test the hypothesis of a more general involvement of SOD1 in ALS.
Main Methods:
- Generation of transgenic mice expressing wild-type human SOD1 at levels comparable to mutant SOD1 in the G93A model.
- Clinical and pathological assessment of the generated mice for ALS-like symptoms and neurodegeneration.
Main Results:
- Mice expressing wild-type human SOD1 developed an ALS-like syndrome and reached terminal illness around 370 days.
- Significant loss of spinal ventral neurons was observed, similar to mutant SOD1 models.
- Aggregated SOD1 was detected in the spinal cords and brains of these mice.
Conclusions:
- Wild-type human SOD1 expression is sufficient to induce an ALS-like disease in mice.
- These findings support the hypothesis that wild-type SOD1 has a more general role in human ALS pathogenesis.
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