title: Persistent activation of p38 mitogen-activated protein kinase in a mouse model of familial amyotrophic lateral sclerosis correlates with disease progression.
abstract: The p38 mitogen-activated protein kinase (p38MAPK) is activated via phosphorylation in neurones and glial cells by a variety of stimuli including oxidative stress, excitotoxicity, and inflammatory cytokines. Activated p38MAPK can in turn induce phosphorylation of cytoskeletal proteins and activation of cytokines and nitric oxide, thus contributing to neurodegeneration. We investigated the expression and distribution of p38MAPK in the spinal cord of transgenic mice expressing a superoxide dismutase 1 mutation (SOD1G93A), a model of familial amyotrophic lateral sclerosis (ALS). Accumulation of p38MAPK was found by immunoblotting in the spinal cord of G93A mice during the progression of disease, but no changes were detected in its mRNA levels. Immunostaining for phosphorylated p38MAPK in lumbar spinal cord sections of SOD1G93A mice at the presymptomatic and early stages of disease showed an increased labeling in motor neurones that colocalized with phosphorylated neurofilaments in vacuolized perikarya and neurites, as detected by confocal microscopy. As the disease progressed, activated p38MAPK also accumulated in hypertrophic astrocytes and reactive microglia, as demonstrated by colocalization with GFAP and CD11b immunostaining, respectively. These data suggest that activation of p38MAPK in motor neurons and then in reactive glial cells may contribute, respectively, to the development and progression of motor neuron pathology in SOD1G93A mice.
authors.affiliation: Laboratory of Molecular Neurobiology, Department of Neuroscience, Istituto di Ricerche Farmacologiche Mario Negri, Milano, Italy. Bendotti@marionegri.it
authors.forename: M
authors.initials: M
authors.lastname: Tortarolo
authors.forename: P
authors.initials: P
authors.lastname: Veglianese
authors.forename: N
authors.initials: N
authors.lastname: Calvaresi
authors.forename: A
authors.initials: A
authors.lastname: Botturi
authors.forename: C
authors.initials: C
authors.lastname: Rossi
authors.forename: A
authors.initials: A
authors.lastname: Giorgini
authors.forename: A
authors.initials: A
authors.lastname: Migheli
authors.forename: C
authors.initials: C
authors.lastname: Bendotti
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D000818:Animals; D001253:Astrocytes / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000235:genetics; D005911:Gliosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D017628:Microglia / Q000378:metabolism / Q000473:pathology; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D009046:Motor Neurons / Q000201:enzymology* / Q000473:pathology; D016501:Neurites / Q000378:metabolism / Q000473:pathology; D016900:Neurofilament Proteins / Q000378:metabolism; D010766:Phosphorylation; D012333:RNA, Messenger / Q000378:metabolism; D013116:Spinal Cord / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D013482:Superoxide Dismutase / Q000172:deficiency* / Q000235:genetics; D000072105:Superoxide Dismutase-1; D015854:Up-Regulation / Q000235:genetics*; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D016900:Neurofilament Proteins; D012333:RNA, Messenger; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases