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.
Ferri, A., Nencini, M., Casciati, A., Cozzolino, M., Angelini, D., Longone, P., et al. (2004). Cell death in amyotrophic lateral sclerosis: interplay between neuronal and glial cells. THE FASEB JOURNAL, 18(11), 1261-1263.
|Tipologia:||Articolo su rivista|
|Citazione:||Ferri, A., Nencini, M., Casciati, A., Cozzolino, M., Angelini, D., Longone, P., et al. (2004). Cell death in amyotrophic lateral sclerosis: interplay between neuronal and glial cells. THE FASEB JOURNAL, 18(11), 1261-1263.|
|IF:||Con Impact Factor ISI|
|Settore Scientifico Disciplinare:||Settore BIO/10|
|Revisione (peer review):||Sì, ma tipo non specificato|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1096/fj.03-1199fje|
|Stato di pubblicazione:||Pubblicato|
|Data di pubblicazione:||ago-2004|
|Titolo:||Cell death in amyotrophic lateral sclerosis: interplay between neuronal and glial cells|
|Autori:||Ferri, A; Nencini, M; Casciati, A; Cozzolino, M; Angelini, D; Longone, P; Spalloni, A; Rotilio, G; Carrì, M|
|Appare nelle tipologie:||01 - Articolo su rivista|