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* Santa Lucia Foundation, Rome, Italy;
Institute of Neurobiology and Molecular Medicine, Consiglio Nazionale della Ricerche (CNR), Rome, Italy;
Department of Psychobiology and Psycopharmacology, Institute of Neuroscience, CNR, Rome, Italy;
Department of Medical Pharmacology, University of Milan, Institute of Neuroscience-CNR, Milan, Italy; and
¶ Department of Biology, University of Rome "Tor Vergata", Italy
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by the selective loss of lower and upper motoneurons. The pathology is imputable in 
2% of cases to mutations in the ubiquitous enzyme Cu, Zn superoxide dismutase (SOD1). Common theories to explain the pathogenic mechanisms of ALS include activation of microglia, responsible for the release of proinflammatory factors. However, how mutant SOD1 affects microglial activation and subsequently injures neurons is still unclear. Considering that extracellular ATP, through purinergic P2 receptors, constitutes a well recognized neuron-to-microglia alarm signal, the aim of this study was to investigate how the expression of mutant SOD1 affects P2 receptor-mediated proinflammatory microglial properties. We used primary and immortalized microglial cells from mutant SOD1 mice to explore several aspects of activation by purinergic ligands and to analyze the overall effect of such stimulation on the viability of NSC-34 and SH-SY5Y neuronal cell lines. We observed up-regulation of P2X4, P2X7, and P2Y6 receptors and down-regulation of ATP-hydrolyzing activities in mutant SOD1 microglia. This potentiation of the purinergic machinery reflected into enhanced sensitivity mainly to 2'-3'-O-(benzoyl-benzoyl) ATP, a P2X7 receptor preferential agonist, and translated into deeper morphological changes, enhancement of TNF-
and cyclooxygenase-2 content, and finally into toxic effects exerted on neuronal cell lines by microglia expressing mutant SOD1. All these parameters were prevented by the antagonist Brilliant Blue G. The purinergic activation of microglia may thus constitute a new route involved in the progression of ALS to be exploited to potentially halt the disease.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by Cofinanziamento Ministero dell’ Università e della Ricerca "Purinoceptors and Neuroprotection" to C.V. and by Ministero della Salute (PF "Meccanismi molecolari e cellulari delle malattie neurodegenerative del sistema motorio") to M.T.C.
2 Address correspondence and reprint requests to Dr. Nadia D’Ambrosi, Fondazione Santa Lucia/CNR, Rome, Italy. E-mail address: n.dambrosi{at}hsantalucia.it
3 Abbreviations used in this paper: ALS, amyotrophic lateral sclerosis; fALS, familial amyotrophic lateral sclerosis; SOD1, Cu,Zn superoxide dismutase; mSOD1, mutant SOD1; hmSOD1, human mSOD1; COX-2, cyclooxigenase 2; BzATP, 2'-3'-O-(benzoyl-benzoyl) ATP; HI, heat inactivated; wt, wild type; BBG, Brilliant Blue G; iMG, immortalised microglia; pMG, primary microgliant; nt, nontransgenic; UDP, uridine diphosphate.
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