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Clinical Testing and Spinal Cord Removal in a Mouse Model for Amyotrophic Lateral Sclerosis (ALS)
Published on: March 17, 2012
Role of matrix metalloproteinase-9 in a mouse model for amyotrophic lateral sclerosis
Maarten Dewil1, Céline Schurmans, Sofie Starckx
1Laboratory for Neurobiology, Campus Gasthuisberg, Herestraat 49, University of Leuven, Minderbroedersstraat 10, B-3000 Leuven, Belgium.
Abstract:
The pathogenesis of amyotrophic lateral sclerosis remains poorly understood, but microglial and astroglial activation are thought to contribute to motor neuron death. Evidence suggests that matrix metalloproteinase-9 (MMP-9) is a mediator of this deleterious effect. In this study, we evaluated the effect of MMP-9 on the pathogenesis of amyotrophic lateral sclerosis. Although marked microglial and astroglial proliferation was seen in the spinal cord and in-vitro studies proved MMP-9 to be produced by these cells, deletion of the MMP-9 gene in SOD1(G93A) mice accelerated rather than delayed the motor neuron disease and significantly reduced survival. Our results suggest that the effect of MMP-9 on mutant superoxide dismutase-1 (SOD1)-induced motor neuron disease is protective rather than hazardous. Therefore, the effect of pharmacological inhibition of MMP-9 activity is unlikely to be of therapeutical benefit in amyotrophic lateral sclerosis.
Insights
Matrix metalloproteinase-9 (MMP-9) plays a protective role in amyotrophic lateral sclerosis (ALS) pathogenesis. Deleting MMP-9 in SOD1(G93A) mice accelerated disease, indicating MMP-9 inhibition is unlikely beneficial for ALS therapy.
Area of Science:
- Neuroscience
- Immunology
- Genetics
Background:
- Amyotrophic lateral sclerosis (ALS) pathogenesis involves microglial and astroglial activation, contributing to motor neuron death.
- Matrix metalloproteinase-9 (MMP-9) has been implicated as a mediator of motor neuron damage in ALS.
- The precise role of MMP-9 in ALS progression requires further investigation.
Purpose of the Study:
- To investigate the specific role of MMP-9 in the pathogenesis of amyotrophic lateral sclerosis.
- To determine whether MMP-9 contributes to or protects against motor neuron degeneration in a mouse model of ALS.
Main Methods:
- Utilized SOD1(G93A) transgenic mice, a model for familial ALS.
- Generated MMP-9 gene-deleted SOD1(G93A) mice to assess the impact of MMP-9 absence.
- Examined microglial and astroglial activation in the spinal cord.
- Conducted in-vitro studies to confirm MMP-9 production by glial cells.
Main Results:
- Significant microglial and astroglial proliferation was observed in the spinal cords of SOD1(G93A) mice.
- In-vitro studies confirmed that microglia and astrocytes produce MMP-9.
- Deletion of the MMP-9 gene in SOD1(G93A) mice accelerated motor neuron disease progression.
- MMP-9 gene deletion significantly reduced the survival rate of SOD1(G93A) mice.
Conclusions:
- MMP-9 exhibits a protective effect, rather than a detrimental one, in mutant superoxide dismutase-1 (SOD1)-induced motor neuron disease.
- Pharmacological inhibition of MMP-9 activity is unlikely to offer therapeutic benefits for amyotrophic lateral sclerosis.
- These findings challenge the existing hypothesis regarding MMP-9's role in ALS pathogenesis.
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