title: Cell death in amyotrophic lateral sclerosis: interplay between neuronal and glial cells.
abstract: Mutations in the gene coding for the ubiquitous, anti-oxidant enzyme Cu,Zn superoxide dismutase (SOD1) are associated with familial amyotrophic lateral sclerosis (fALS), a fatal disease characterized by selective loss of motor neurons. Expression of a mutant SOD1 typical of fALS patients restricted to either motor neurons or astrocytes is insufficient to generate a pathological phenotype in mouse models, suggesting that a deleterious interplay between different cell types is necessary for the pathogenesis of the disease. In this study, we demonstrate the actual role of a functional cross-talk between glial and neuronal cells expressing fALS mutant G93A-SOD1, where an increase in the production of reactive oxygen species occurs. We show that human glioblastoma cells expressing G93A-SOD1 induce activation of caspase-1, release of cytokines, and activation of apoptotic pathways in cocultured human neuroblastoma cells also expressing G93A-SOD1. Activation of caspase-1 and caspase-3 is observed also in neuroblastoma lines expressing other fALS-SOD1s (G37R, G85R, and I113T) cocultured with glioblastoma lines expressing the corresponding mutant enzymes. These effects are consequent to activation of inflammatory processes in G93A-glioblastoma cells stimulated by cocultured G93A-neuroblastoma. Furthermore, selective death of embryonal spinal motor neurons from G93A-SOD1 transgenic mice is induced by coculture with G93A-glioblastoma and prevented by inhibition of NO synthase. Proinflammatory cytokines, interferon-gamma, and nitric oxide are among the molecular signals exchanged between glial and neuronal cells that generate a functional interplay between the two cell types. This cross-talk may be crucial for the pathogenesis of SOD1-linked fALS but also for the more common sporadic form of the disease, where markers of increased oxidative stress and of glial activation have been found.
authors.affiliation: Istituto di Neuroscienze CNR, Sez. Psicobiologia e Psicofarmacologia, Mondino-Tor Vergata-S. Lucià, Rome, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Ferri
authors.forename: Monica
authors.initials: M
authors.lastname: Nencini
authors.forename: Arianna
authors.initials: A
authors.lastname: Casciati
authors.forename: Mauro
authors.initials: M
authors.lastname: Cozzolino
authors.forename: Daniela F
authors.initials: DF
authors.lastname: Angelini
authors.forename: Patrizia
authors.initials: P
authors.lastname: Longone
authors.forename: Alida
authors.initials: A
authors.lastname: Spalloni
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Rotilio
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Carrì
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D020170:Caspase 1 / Q000378:metabolism; D002374:Catalase / Q000032:analysis; D002450:Cell Communication / Q000502:physiology*; D018920:Coculture Techniques; D016207:Cytokines / Q000378:metabolism; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005909:Glioblastoma / Q000473:pathology; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D016472:Motor Neuron Disease / Q000473:pathology*; D009046:Motor Neurons / Q000473:pathology; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009447:Neuroblastoma / Q000473:pathology; D009457:Neuroglia / Q000473:pathology*; D009474:Neurons / Q000473:pathology*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D009603:Nitroso Compounds / Q000494:pharmacology; D018384:Oxidative Stress; D017382:Reactive Oxygen Species; D013116:Spinal Cord / Q000166:cytology / Q000196:embryology; D013482:Superoxide Dismutase / Q000235:genetics / Q000502:physiology*; D000072105:Superoxide Dismutase-1; D014162:Transfection
chemical_list: D016207:Cytokines; D004791:Enzyme Inhibitors; D008070:Lipopolysaccharides; C093285:NOC 18; D020030:Nitric Oxide Donors; D009603:Nitroso Compounds; D017382:Reactive Oxygen Species; C000606290:SOD1 protein, human; D007371:Interferon-gamma; D002374:Catalase; D019001:Nitric Oxide Synthase; C109415:SOD1 G93A protein; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D020170:Caspase 1; D019331:NG-Nitroarginine Methyl Ester