Hartman Institute for Therapeutic Organ Regeneration

Matrix metalloproteinase-9 regulates TNF-alpha and FasL expression in neuronal, glial cells and its absence extends life in a transgenic mouse model of amyotrophic lateral sclerosis.

TitleMatrix metalloproteinase-9 regulates TNF-alpha and FasL expression in neuronal, glial cells and its absence extends life in a transgenic mouse model of amyotrophic lateral sclerosis.
Publication TypeJournal Article
Year of Publication2007
AuthorsKiaei M, Kipiani K, Calingasan NY, Wille E, Chen J, Heissig B, Rafii S, Lorenzl S, M Beal F
JournalExp Neurol
Volume205
Issue1
Pagination74-81
Date Published2007 May
ISSN0014-4886
KeywordsADAM Proteins, ADAM17 Protein, Alanine, Amyotrophic Lateral Sclerosis, Animals, Fas Ligand Protein, Glycine, Humans, Immunologic Techniques, Longevity, Male, Matrix Metalloproteinase 9, Mice, Mice, Inbred Strains, Mice, Transgenic, Mutation, Nervous System, Neuroglia, Neurons, Staining and Labeling, Superoxide Dismutase, Superoxide Dismutase-1, Tumor Necrosis Factor-alpha
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.

DOI10.1016/j.expneurol.2007.01.036
Alternate JournalExp Neurol
PubMed ID17362932

Weill Cornell Medicine
Hartman Institute for Therapeutic Organ Regeneration
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