Title |
Extracellular ATP and the P2X7receptor in astrocyte-mediated motor neuron death: implications for amyotrophic lateral sclerosis
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Published in |
Journal of Neuroinflammation, June 2010
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DOI | 10.1186/1742-2094-7-33 |
Pubmed ID | |
Authors |
Mandi Gandelman, Hugo Peluffo, Joseph S Beckman, Patricia Cassina, Luis Barbeito |
Abstract |
During pathology of the nervous system, increased extracellular ATP acts both as a cytotoxic factor and pro-inflammatory mediator through P2X(7) receptors. In animal models of amyotrophic lateral sclerosis (ALS), astrocytes expressing superoxide dismutase 1 (SOD1G93A) mutations display a neuroinflammatory phenotype and contribute to disease progression and motor neuron death. Here we studied the role of extracellular ATP acting through P2X(7) receptors as an initiator of a neurotoxic phenotype that leads to astrocyte-mediated motor neuron death in non-transgenic and SOD1G93A astrocytes. We evaluated motor neuron survival after co-culture with SOD1G93A or non-transgenic astrocytes pretreated with agents known to modulate ATP release or P2X(7) receptor. We also characterized astrocyte proliferation and extracellular ATP degradation. Repeated stimulation by ATP or the P2X(7)-selective agonist BzATP caused astrocytes to become neurotoxic, inducing death of motor neurons. Involvement of P2X(7) receptor was further confirmed by Brilliant blue G inhibition of ATP and BzATP effects. In SOD1G93A astrocyte cultures, pharmacological inhibition of P2X(7) receptor or increased extracellular ATP degradation with the enzyme apyrase was sufficient to completely abolish their toxicity towards motor neurons. SOD1G93A astrocytes also displayed increased ATP-dependent proliferation and a basal increase in extracellular ATP degradation. Here we found that P2X(7) receptor activation in spinal cord astrocytes initiated a neurotoxic phenotype that leads to motor neuron death. Remarkably, the neurotoxic phenotype of SOD1G93A astrocytes depended upon basal activation the P2X(7) receptor. Thus, pharmacological inhibition of P2X(7) receptor might reduce neuroinflammation in ALS through astrocytes. |
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Unknown | 160 | 97% |
Demographic breakdown
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Student > Master | 27 | 16% |
Researcher | 21 | 13% |
Student > Doctoral Student | 13 | 8% |
Student > Bachelor | 9 | 5% |
Other | 26 | 16% |
Unknown | 26 | 16% |
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Neuroscience | 30 | 18% |
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Medicine and Dentistry | 15 | 9% |
Immunology and Microbiology | 5 | 3% |
Other | 12 | 7% |
Unknown | 34 | 21% |