NADPH oxidase (NOX2) activity is a modifier of survival in ALS
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NADPH-oxidases (NOX) catalyze the formation of reactive oxygen species (ROS), which play a role in the development of neurological diseases, particularly those generated by the phagocytic isoform NOX2. Increased ROS has been observed in the amyotrophic lateral sclerosis (ALS) SOD1 transgenic mouse, and in this preclinical model the inactivation of NOX2 decreases ROS production and extends survival. Our aim was to evaluate NOX2 activity measuring neutrophil oxidative burst in a cohort of 83 ALS patients, and age- and gender-matched healthy controls. Oxidative burst was measured directly in fresh blood using Phagoburst™ assay by flow cytometry. Mean fluorescence intensity (MFI), emitted in response to different stimuli, leads to produce ROS and corresponds to the percentage of oxidizing cells and their enzymatic activity (GeoMean). No difference was found between the MFI values in cases and controls. NOX2 activity was independent from gender and age, and in patients was not related to disease duration, site of onset (bulbar vs. spinal), or ALSFRS-R score. However, patients with a NOX2 activity lower than the median value showed a 1-year increase of survival from onset (p = 0.011). The effect of NOX2 was independent from other known prognostic factors. These findings are in keeping with the observations in the mouse model of ALS, and demonstrate the strong role of NOX2 in modifying progression in ALS patients. A proper modulation of NOX2 activity might hold therapeutic potential for ALS.
KeywordsALS NADPH oxidase NOX2 ROS Survival
We thank the patient and her family for having collaborated to this study; his work was funded by grants of the European Community’s Framework Programme (FP7/2007-2013, under Grants Agreement 278611 and 259867), the Joint Programme—Neurodegenerative Disease Research granted by Italian Ministry of Health (Sophia Project), the Italian Ministry of Health (Ministero della Salute, Ricerca Sanitaria Finalizzata, 2010, Grant RF-2010-2309849), and by Fondazione Magnetto Onlus. Funding organizations had no role in design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript.
Conflicts of interest
Dr. Marrali reports no disclosure. Dr. Casale reports no disclosure. Dr. Salamone reports no disclosure. Dr. Caorsi reports no disclosure. Prof. Amoroso reports no disclosure. Dr. Brunetti reports no disclosure. Dr. Restagno has received research support from Italian Ministry of Health (Ricerca Finalizzata) and Regione Piemonte (Ricerca Finalizzata). Dr. Barberis reports no disclosure. Dr. Bertuzzo reports no disclosure. Dr. Canosa reports no disclosure. Dr. Moglia reports no disclosure. Dr. Calvo has received research support from Italian Ministry of Health (Ricerca Finalizzata). Dr. Chiò serves on the editorial advisory board of Amyotrophic Lateral Sclerosis and has received research support from Italian Ministry of Health (Ricerca Finalizzata), Regione Piemonte (Ricerca Finalizzata), University of Torino, Federazione Italiana Giuoco Calcio, Fondazione Vialli e Mauro onlus, and European Commission (Health Seventh Framework Programme); he serves on scientific advisory boards for Biogen Idec and Cytokinetics.
This study has been approved by the appropriate ethics committee and has therefore been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki.
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