Inflammation and oxidative stress are thought to play determinant roles in the pathogenesis of amyotrophic lateral sclerosis (ALS). Degenerating motor neurons produce signals that activate microglia to release reactive oxygen species (ROS) and proinflammatory cytokines, resulting in a vicious cycle of neurodegeneration. The ALS-causing mutant protein Cu+/Zn+ superoxide dismutase SOD1- G93A directly enhances the activity of the main ROS-producing enzyme in microglia, NADPH oxidase 2 (NOX2), a well-known player in the pathogenesis of ALS. Considering that extracellular ATP through P2X7 receptor constitutes a neuron-to-microglia alarm signal implicated in ALS pathology, we used primary microglial cells derived from transgenic SOD1-G93A mice and SOD1-G93A mice lacking the P2X7 receptor to investigate the effects of both pharmacological induction and genetic ablation of receptor activity on the NOX2 pathway. We observed that, in SOD1-G93A microglia, the stimulation of P2X7 receptor by 29-39- O-(benzoyl-benzoyl) ATP enhanced NOX2 activity in terms of translocation of p67phox to the membrane and ROS production; this effect was totally dependent on Rac1.We also found that, following P2X7 receptor stimulation, the phosphorylation of ERK1/2 was augmented in ALS microglia, and there was a mutual dependency between the NOX2 and ERK1/2 pathways. All of these microglia-mediated damaging mechanisms were prevented by knocking out P2X7 receptor and by the use of specific antagonists. These findings suggest a noxious mechanism by which P2X7 receptor leads to enhanced oxidative stress in ALS microglia and identify the P2X7 receptor as a promising target for the development of therapeutic strategies to slow down the progression of ALS.

Apolloni, S., Parisi, C., Pesaresi, M. G., Rossi, S., Carri', M. T., Cozzolino, M., Volonte', C., D'Ambrosi, N., The NADPH Oxidase Pathway Is Dysregulated by the P2X7 Receptor in the SOD1-G93A Microglia Model ofAmyotrophic Lateral Sclerosis, <<JOURNAL OF IMMUNOLOGY>>, 2013; 2013/190 (Maggio/9): N/A-N/A. [doi:10.4049/jimmunol.1203262] [http://hdl.handle.net/10807/43308]

The NADPH Oxidase Pathway Is Dysregulated by the P2X7 Receptor in the SOD1-G93A Microglia Model of Amyotrophic Lateral Sclerosis

D'Ambrosi, Nadia
2013

Abstract

Inflammation and oxidative stress are thought to play determinant roles in the pathogenesis of amyotrophic lateral sclerosis (ALS). Degenerating motor neurons produce signals that activate microglia to release reactive oxygen species (ROS) and proinflammatory cytokines, resulting in a vicious cycle of neurodegeneration. The ALS-causing mutant protein Cu+/Zn+ superoxide dismutase SOD1- G93A directly enhances the activity of the main ROS-producing enzyme in microglia, NADPH oxidase 2 (NOX2), a well-known player in the pathogenesis of ALS. Considering that extracellular ATP through P2X7 receptor constitutes a neuron-to-microglia alarm signal implicated in ALS pathology, we used primary microglial cells derived from transgenic SOD1-G93A mice and SOD1-G93A mice lacking the P2X7 receptor to investigate the effects of both pharmacological induction and genetic ablation of receptor activity on the NOX2 pathway. We observed that, in SOD1-G93A microglia, the stimulation of P2X7 receptor by 29-39- O-(benzoyl-benzoyl) ATP enhanced NOX2 activity in terms of translocation of p67phox to the membrane and ROS production; this effect was totally dependent on Rac1.We also found that, following P2X7 receptor stimulation, the phosphorylation of ERK1/2 was augmented in ALS microglia, and there was a mutual dependency between the NOX2 and ERK1/2 pathways. All of these microglia-mediated damaging mechanisms were prevented by knocking out P2X7 receptor and by the use of specific antagonists. These findings suggest a noxious mechanism by which P2X7 receptor leads to enhanced oxidative stress in ALS microglia and identify the P2X7 receptor as a promising target for the development of therapeutic strategies to slow down the progression of ALS.
2013
Inglese
Apolloni, S., Parisi, C., Pesaresi, M. G., Rossi, S., Carri', M. T., Cozzolino, M., Volonte', C., D'Ambrosi, N., The NADPH Oxidase Pathway Is Dysregulated by the P2X7 Receptor in the SOD1-G93A Microglia Model ofAmyotrophic Lateral Sclerosis, <<JOURNAL OF IMMUNOLOGY>>, 2013; 2013/190 (Maggio/9): N/A-N/A. [doi:10.4049/jimmunol.1203262] [http://hdl.handle.net/10807/43308]
File in questo prodotto:
Non ci sono file associati a questo prodotto.

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/10807/43308
Citazioni
  • ???jsp.display-item.citation.pmc??? ND
  • Scopus 94
  • ???jsp.display-item.citation.isi??? 90
social impact