title: Serum matrix metalloproteinase-9 activity is dysregulated with disease progression in the mutant SOD1 transgenic mice.
abstract: Amyotrophic lateral sclerosis (ALS) is an adult-onset fatal neurodegenerative disorder characterized by progressive deterioration of motor neurons in the spinal cord, brainstem, and cerebral cortex. Matrix metalloproteinase-9 (MMP-9) is proposed to be a biomarker for ALS due to a potential pathological role in the disease. However, despite numerous studies, it is still unclear whether there is a direct correlation between MMP-9 expression in serum and progression of disease. Therefore, we used a TgSOD1(G93A) mouse with a low transgene copy number. This model shows slow disease progression analogous to human ALS and provides a useful model to study biomarker expression at different stages of disease. Using zymography, we found that serum MMP-9 activity was significantly elevated in animals showing early signs of disease when compared to the younger, pre-symptomatic animals. This was followed by a decrease in MMP-9 activity in TgSOD1(G93A) mice with end-stage disease. These results were confirmed in serum of a high copy number strain of TgSOD1(G93A) mice with rapid progression. MMP-9 expression was changed accordingly in spinal motor neurons, glia and neuropil, suggesting a spinal cord contribution to blood MMP-9 activity. Serum MMP-2 activity followed a similar profile as the MMP-9 in these two models. These data indicate that circulating MMP-9 is altered throughout the course of disease progression in mice. Further studies in human ALS may validate the suitability of serum MMP-9 activity as a biomarker for early stage disease.
authors.affiliation: Department of Pathology, The University of Melbourne, Parkville, Vic. 3010, Australia.
authors.forename: Cynthia P W
authors.initials: CP
authors.lastname: Soon
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Crouch
authors.forename: Bradley J
authors.initials: BJ
authors.lastname: Turner
authors.forename: Catriona A
authors.initials: CA
authors.lastname: McLean
authors.forename: Katrina M
authors.initials: KM
authors.lastname: Laughton
authors.forename: Julie D
authors.initials: JD
authors.lastname: Atkin
authors.forename: Colin L
authors.initials: CL
authors.lastname: Masters
authors.forename: Anthony R
authors.initials: AR
authors.lastname: White
authors.forename: Qiao-Xin
authors.initials: QX
authors.lastname: Li
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000097:blood* / Q000175:diagnosis / Q000201:enzymology*; D000818:Animals; D015415:Biomarkers / Q000032:analysis / Q000097:blood; D004195:Disease Models, Animal; D018450:Disease Progression; D018628:Gene Dosage / Q000235:genetics; D015971:Gene Expression Regulation, Enzymologic / Q000235:genetics; D020022:Genetic Predisposition to Disease; D020778:Matrix Metalloproteinase 2 / Q000032:analysis / Q000097:blood; D020780:Matrix Metalloproteinase 9 / Q000032:analysis / Q000097:blood*; D051379:Mice; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000201:enzymology* / Q000473:pathology; D009154:Mutation / Q000235:genetics; D009457:Neuroglia / Q000201:enzymology; D013116:Spinal Cord / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D013482:Superoxide Dismutase / Q000235:genetics; D000072105:Superoxide Dismutase-1
chemical_list: D015415:Biomarkers; C000606290:SOD1 protein, human; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9