Abstract
Whether increased levels of matrix metalloproteinases (MMPs) correspond to a role in the pathogenesis of amyotrophic lateral sclerosis (ALS) needs to be determined and it is actively being pursued. Here we present evidence suggesting that MMP-9 contributes to the motor neuron cell death in ALS. We examined the role of MMP-9 in a mouse model of familial ALS and found that lack of MMP-9 increased survival (31%) in G93A SOD1 mice. Also, MMP-9 deficiency in G93A mice significantly attenuated neuronal loss, and reduced neuronal TNF-alpha and FasL immunoreactivities in the lumbar spinal cord. These findings suggest that MMP-9 is an important player in the pathogenesis of ALS. Our data suggest that the mechanism for MMP-9 neurotoxicity in ALS may be by upregulating neuronal TNF-alpha and FasL expression and activation. This study provides new mechanism and suggests that MMP inhibitors may offer a new therapeutic strategy for ALS.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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ADAM Proteins
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ADAM17 Protein
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Alanine
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Amyotrophic Lateral Sclerosis / metabolism
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Amyotrophic Lateral Sclerosis / pathology
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Amyotrophic Lateral Sclerosis / physiopathology*
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Animals
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Fas Ligand Protein / metabolism*
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Glycine
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Humans
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Immunologic Techniques
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Longevity*
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Male
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Matrix Metalloproteinase 9 / deficiency*
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Matrix Metalloproteinase 9 / metabolism*
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Mice
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Mice, Inbred Strains
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Mice, Transgenic
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Mutation
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Nervous System / metabolism*
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Nervous System / pathology
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Neuroglia / metabolism
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Neurons / metabolism
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Staining and Labeling
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Superoxide Dismutase / genetics
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Superoxide Dismutase-1
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Tumor Necrosis Factor-alpha / metabolism*
Substances
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Fas Ligand Protein
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SOD1 protein, human
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Tumor Necrosis Factor-alpha
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Sod1 protein, mouse
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Superoxide Dismutase
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Superoxide Dismutase-1
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ADAM Proteins
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Matrix Metalloproteinase 9
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ADAM17 Protein
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Alanine
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Glycine