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.
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.
Kiaei
Mahmoud
M
Department of Neurology and Neuroscience, Weill Medical College of Cornell University, 525 East 68th Street, New York, NY 10021, USA. mak2026@med.cornell.edu <mak2026@med.cornell.edu>
Kipiani
Khatuna
K
Calingasan
Noel Y
NY
Wille
Elizabeth
E
Chen
Junyu
J
Heissig
Beate
B
Rafii
Shahin
S
Lorenzl
Stefan
S
Beal
M Flint
MF
D051722:ADAM Proteins; D000072198:ADAM17 Protein; D000409:Alanine; D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D000818:Animals; D053222:Fas Ligand Protein / Q000378:metabolism*; D005998:Glycine; D006801:Humans; D007158:Immunologic Techniques; D008136:Longevity; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000172:deficiency* / Q000378:metabolism*; D051379:Mice; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D009154:Mutation; D009420:Nervous System / Q000378:metabolism* / Q000473:pathology; D009457:Neuroglia / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D013194:Staining and Labeling; D013482:Superoxide Dismutase / Q000235:genetics; D000072105:Superoxide Dismutase-1; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D053222:Fas Ligand Protein; C000606290:SOD1 protein, human; D014409:Tumor Necrosis Factor-alpha; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D051722:ADAM Proteins; D020780:Matrix Metalloproteinase 9; D000072198:ADAM17 Protein; D000409:Alanine; D005998:Glycine