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

• Published in: Experimental neurology 2007-05, Vol.205 (1), p.74-81
• Main Authors: Kiaei, Mahmoud, Kipiani, Khatuna, Calingasan, Noel Y., Wille, Elizabeth, Chen, Junyu, Heissig, Beate, Rafii, Shahin, Lorenzl, Stefan, Beal, M. Flint
• Format: Article
• Language: English
• Subjects: ADAM Proteins; ADAM17 Protein; Alanine; ALS; Amyotrophic Lateral Sclerosis - metabolism; Amyotrophic Lateral Sclerosis - pathology; Amyotrophic Lateral Sclerosis - physiopathology; Animals; Biological and medical sciences; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Fas ligand; Fas Ligand Protein - metabolism; Glycine; Humans; Immunologic Techniques; Longevity; Male; Matrix Metalloproteinase 9 - deficiency; Matrix Metalloproteinase 9 - metabolism; Medical sciences; Mice; Mice, Inbred Strains; Mice, Transgenic; MMP-9; Motor neuron disease; Multiple sclerosis and variants. Guillain barré syndrome and other inflammatory polyneuropathies. Leukoencephalitis; Mutant SOD1; Mutation; Nervous System - metabolism; Nervous System - pathology; Neuroglia - metabolism; Neurology; Neurons - metabolism; Staining and Labeling; Superoxide Dismutase - genetics; Superoxide Dismutase-1; TNF-α; Tumor Necrosis Factor-alpha - metabolism
• ISSN: 0014-4886; 1090-2430
• DOI: 10.1016/j.expneurol.2007.01.036

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-α 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-α and FasL expression and activation. This study provides new mechanism and suggests that MMP inhibitors may offer a new therapeutic strategy for ALS.