Skip to main content
Top
Published in: Journal of Neurology 11/2014

01-11-2014 | Original Communication

NADPH oxidase (NOX2) activity is a modifier of survival in ALS

Authors: Giuseppe Marrali, Federico Casale, Paolina Salamone, Giuseppe Fuda, Cristiana Caorsi, Antonio Amoroso, Maura Brunetti, Gabriella Restagno, Marco Barberis, Davide Bertuzzo, Antonio Canosa, Cristina Moglia, Andrea Calvo, Adriano Chiò

Published in: Journal of Neurology | Issue 11/2014

Login to get access

Abstract

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.
Appendix
Available only for authorised users
Literature
3.
go back to reference Beghi E, Chiò A, Couratier P et al (2011) The epidemiology and treatment of ALS: focus on the heterogeneity of the disease and critical appraisal of therapeutic trials. Amyotroph Lateral Scler 12:1–10PubMedCentralCrossRefPubMed Beghi E, Chiò A, Couratier P et al (2011) The epidemiology and treatment of ALS: focus on the heterogeneity of the disease and critical appraisal of therapeutic trials. Amyotroph Lateral Scler 12:1–10PubMedCentralCrossRefPubMed
4.
go back to reference Turner MR, Hardiman O, Benatar M et al (2013) Controversies and priorities in amyotrophic lateral sclerosis. Lancet Neurol 12:310–322CrossRefPubMed Turner MR, Hardiman O, Benatar M et al (2013) Controversies and priorities in amyotrophic lateral sclerosis. Lancet Neurol 12:310–322CrossRefPubMed
5.
go back to reference Wu DC, Ré DB, Nagai M, Ischiropoulos H, Przedborski S (2006) The inflammatory NADPH oxidase enzyme modulates motor neuron degeneration in amyotrophic lateral sclerosis mice. Proc Nat Aca Sci USA 103:12132–12137CrossRef Wu DC, Ré DB, Nagai M, Ischiropoulos H, Przedborski S (2006) The inflammatory NADPH oxidase enzyme modulates motor neuron degeneration in amyotrophic lateral sclerosis mice. Proc Nat Aca Sci USA 103:12132–12137CrossRef
7.
go back to reference Kimura F, Fujimura C, Ishida S et al (2006) Progression rate of ALSFRS-R at time of diagnosis predicts survival time in ALS. Neurology 66:265–267CrossRefPubMed Kimura F, Fujimura C, Ishida S et al (2006) Progression rate of ALSFRS-R at time of diagnosis predicts survival time in ALS. Neurology 66:265–267CrossRefPubMed
8.
go back to reference Mander PK, Jekabsone A, Brown GC (2006) Microglia proliferation is regulated by hydrogen peroxide from NADPH oxidase. J Immunol 176:1046–1052CrossRefPubMed Mander PK, Jekabsone A, Brown GC (2006) Microglia proliferation is regulated by hydrogen peroxide from NADPH oxidase. J Immunol 176:1046–1052CrossRefPubMed
9.
go back to reference Qin L, Liu Y, Wang T et al (2004) NADPH oxidase mediates lipopolysaccharide-induced neurotoxicity and proinflammatory gene expression in activated microglia. J Biol Chem 279:1415–1421CrossRefPubMed Qin L, Liu Y, Wang T et al (2004) NADPH oxidase mediates lipopolysaccharide-induced neurotoxicity and proinflammatory gene expression in activated microglia. J Biol Chem 279:1415–1421CrossRefPubMed
10.
go back to reference Pawate S, Shen Q, Fan F, Bhat NR (2004) Redox regulation of glial inflammatory response to lipopolysaccharide and interferon gamma. J Neurosci Res 77:540–551CrossRefPubMed Pawate S, Shen Q, Fan F, Bhat NR (2004) Redox regulation of glial inflammatory response to lipopolysaccharide and interferon gamma. J Neurosci Res 77:540–551CrossRefPubMed
11.
go back to reference Sorce S, Krause K-H, Jaquet V (2012) Targeting NOX enzymes in the central nervous system: therapeutic opportunities. Cell Mol Life Sci 69:2387–2407CrossRefPubMed Sorce S, Krause K-H, Jaquet V (2012) Targeting NOX enzymes in the central nervous system: therapeutic opportunities. Cell Mol Life Sci 69:2387–2407CrossRefPubMed
12.
go back to reference Anilkumar N, Weber R, Zhang M, Brewer A, Shah AM (2008) Nox4 and nox2 NADPH oxidases mediate distinct cellular redox signaling responses to agonist stimulation. Arterioscler Thromb Vasc Biol 28:1347–1354CrossRefPubMed Anilkumar N, Weber R, Zhang M, Brewer A, Shah AM (2008) Nox4 and nox2 NADPH oxidases mediate distinct cellular redox signaling responses to agonist stimulation. Arterioscler Thromb Vasc Biol 28:1347–1354CrossRefPubMed
13.
go back to reference Li Q, Spencer NY, Oakley FD, Buettner GR, Engelhardt JF (2009) Endosomal Nox2 facilitates redox-dependent induction of NF-kappaB by TNF-alpha. Antioxid Redox Signal 11:1249–1263PubMedCentralCrossRefPubMed Li Q, Spencer NY, Oakley FD, Buettner GR, Engelhardt JF (2009) Endosomal Nox2 facilitates redox-dependent induction of NF-kappaB by TNF-alpha. Antioxid Redox Signal 11:1249–1263PubMedCentralCrossRefPubMed
14.
go back to reference Leto TL, Morand S, Hurt D, Ueyama T (2009) Targeting and regulation of reactive oxygen species generation by Nox family NADPH oxidases. Antioxid Redox Signal 11:2607–2619PubMedCentralCrossRefPubMed Leto TL, Morand S, Hurt D, Ueyama T (2009) Targeting and regulation of reactive oxygen species generation by Nox family NADPH oxidases. Antioxid Redox Signal 11:2607–2619PubMedCentralCrossRefPubMed
15.
go back to reference Lambeth JD, Krause KH, Clark RA (2008) NOX enzymes as novel targets for drug development. Semin Immunopathol 30:339–363CrossRefPubMed Lambeth JD, Krause KH, Clark RA (2008) NOX enzymes as novel targets for drug development. Semin Immunopathol 30:339–363CrossRefPubMed
16.
go back to reference Dinauer MC, Orkin SH, Brown R, Jesaitis AJ, Parkos CA (1987) The glycoprotein encoded by the X-linked chronic granulomatous disease locus is a component of the neutrophil cytochrome b complex. Nature 327:717–720CrossRefPubMed Dinauer MC, Orkin SH, Brown R, Jesaitis AJ, Parkos CA (1987) The glycoprotein encoded by the X-linked chronic granulomatous disease locus is a component of the neutrophil cytochrome b complex. Nature 327:717–720CrossRefPubMed
17.
go back to reference Sankarapandi S, Zweier JL, Mukherjee G, Quinn MT, Huso DL (1998) Measurement and characterization of superoxide generation in microglial cells: evidence for an NADPH oxidase-dependent pathway. Arch Biochem Biophys 353:312–321CrossRefPubMed Sankarapandi S, Zweier JL, Mukherjee G, Quinn MT, Huso DL (1998) Measurement and characterization of superoxide generation in microglial cells: evidence for an NADPH oxidase-dependent pathway. Arch Biochem Biophys 353:312–321CrossRefPubMed
19.
go back to reference Babior BM (1978) Oxygen-dependent microbial killing by phagocytes (first of two parts). N Engl J Med 298:659–668CrossRefPubMed Babior BM (1978) Oxygen-dependent microbial killing by phagocytes (first of two parts). N Engl J Med 298:659–668CrossRefPubMed
20.
go back to reference Jekabsone A, Mander PK, Tickler A, Sharpe M, Brown GC (2006) Fibrillar beta-amyloid peptide Abeta1-40 activates microglial proliferation via stimulating TNF-alpha release and H2O2 derived from NADPH oxidase: a cell culture study. J Neuroinflamm 3:24CrossRef Jekabsone A, Mander PK, Tickler A, Sharpe M, Brown GC (2006) Fibrillar beta-amyloid peptide Abeta1-40 activates microglial proliferation via stimulating TNF-alpha release and H2O2 derived from NADPH oxidase: a cell culture study. J Neuroinflamm 3:24CrossRef
21.
go back to reference Heyworth PG, Cross AR, Curnutte JT (2003) Chronic granulomatous disease. Curr Opin Immunol 2003(15):578–584CrossRef Heyworth PG, Cross AR, Curnutte JT (2003) Chronic granulomatous disease. Curr Opin Immunol 2003(15):578–584CrossRef
22.
go back to reference Appel SH, Beers DR, Henkel JS (2010) T cell-microglial dialogue in Parkinson’s disease and amyotrophic lateral sclerosis: are we listening? Trends Immunol 31:7–17PubMedCentralCrossRefPubMed Appel SH, Beers DR, Henkel JS (2010) T cell-microglial dialogue in Parkinson’s disease and amyotrophic lateral sclerosis: are we listening? Trends Immunol 31:7–17PubMedCentralCrossRefPubMed
23.
go back to reference Hald A, Van Beek J, Lotharius J (2007) Inflammation in Parkinson’s disease: causative or epiphenomenal? Subcell Biochem 42:249–279CrossRefPubMed Hald A, Van Beek J, Lotharius J (2007) Inflammation in Parkinson’s disease: causative or epiphenomenal? Subcell Biochem 42:249–279CrossRefPubMed
25.
go back to reference Bowerman M, Vincent T, Scamps F, Perrin FE, Camu W, Raoul C (2013) Neuroimmunity dynamics and the development of therapeutic strategies for amyotrophic lateral sclerosis. Front Cell Neurosci 19(7):214 Bowerman M, Vincent T, Scamps F, Perrin FE, Camu W, Raoul C (2013) Neuroimmunity dynamics and the development of therapeutic strategies for amyotrophic lateral sclerosis. Front Cell Neurosci 19(7):214
27.
go back to reference Kabashi E, Valdmanis PN, Dion P, Rouleau GA (2007) Oxidized/misfolded superoxide dismutase-1: the cause of all amyotrophic lateral sclerosis? Ann Neurol 62:553–559CrossRefPubMed Kabashi E, Valdmanis PN, Dion P, Rouleau GA (2007) Oxidized/misfolded superoxide dismutase-1: the cause of all amyotrophic lateral sclerosis? Ann Neurol 62:553–559CrossRefPubMed
28.
go back to reference Cereda C, Leoni E, Milani P et al (2013) Altered intracellular localization of SOD1 in leukocytes from patients with sporadic amyotrophic lateral sclerosis. PLoS ONE 8:e75916PubMedCentralCrossRefPubMed Cereda C, Leoni E, Milani P et al (2013) Altered intracellular localization of SOD1 in leukocytes from patients with sporadic amyotrophic lateral sclerosis. PLoS ONE 8:e75916PubMedCentralCrossRefPubMed
29.
go back to reference Synofzik M, Ronchi D, Keskin I et al (2012) Mutant superoxide dismutase-1 indistinguishable from wild-type causes ALS. Hum Mol Genet 21:3568–3574CrossRefPubMed Synofzik M, Ronchi D, Keskin I et al (2012) Mutant superoxide dismutase-1 indistinguishable from wild-type causes ALS. Hum Mol Genet 21:3568–3574CrossRefPubMed
Metadata
Title
NADPH oxidase (NOX2) activity is a modifier of survival in ALS
Authors
Giuseppe Marrali
Federico Casale
Paolina Salamone
Giuseppe Fuda
Cristiana Caorsi
Antonio Amoroso
Maura Brunetti
Gabriella Restagno
Marco Barberis
Davide Bertuzzo
Antonio Canosa
Cristina Moglia
Andrea Calvo
Adriano Chiò
Publication date
01-11-2014
Publisher
Springer Berlin Heidelberg
Published in
Journal of Neurology / Issue 11/2014
Print ISSN: 0340-5354
Electronic ISSN: 1432-1459
DOI
https://doi.org/10.1007/s00415-014-7470-0

Other articles of this Issue 11/2014

Journal of Neurology 11/2014 Go to the issue