Skip to main content

Advertisement

Springer Nature Link
Log in

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

  • Original Communication
  • Published:
Journal of Neurology Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

Explore related subjects

Discover the latest articles and news from researchers in related subjects, suggested using machine learning.

References

  1. Chiò A, Calvo A, Mazzini L et al (2012) Extensive genetics of ALS: a population-based study in Italy. Neurology 79:1983–1989

    Article  PubMed Central  PubMed  Google Scholar 

  2. Renton AE, Chiò A, Traynor BJ (2014) State of play in amyotrophic lateral sclerosis genetics. Nat Neurosci 17:17–23

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  3. 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 12:1–10

    Article  PubMed Central  PubMed  Google Scholar 

  4. Turner MR, Hardiman O, Benatar M et al (2013) Controversies and priorities in amyotrophic lateral sclerosis. Lancet Neurol 12:310–322

    Article  CAS  PubMed  Google Scholar 

  5. 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 103:12132–12137

    Article  CAS  Google Scholar 

  6. Marden JJ, Harraz MM, Williams AJ et al (2007) Redox modifier genes in amyotrophic lateral sclerosis in mice. J Clin Invest 117:2913–2919

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  7. Kimura F, Fujimura C, Ishida S et al (2006) Progression rate of ALSFRS-R at time of diagnosis predicts survival time in ALS. Neurology 66:265–267

    Article  CAS  PubMed  Google Scholar 

  8. Mander PK, Jekabsone A, Brown GC (2006) Microglia proliferation is regulated by hydrogen peroxide from NADPH oxidase. J Immunol 176:1046–1052

    Article  CAS  PubMed  Google Scholar 

  9. 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 279:1415–1421

    Article  CAS  PubMed  Google Scholar 

  10. Pawate S, Shen Q, Fan F, Bhat NR (2004) Redox regulation of glial inflammatory response to lipopolysaccharide and interferon gamma. J Neurosci Res 77:540–551

    Article  CAS  PubMed  Google Scholar 

  11. Sorce S, Krause K-H, Jaquet V (2012) Targeting NOX enzymes in the central nervous system: therapeutic opportunities. Cell Mol Life Sci 69:2387–2407

    Article  CAS  PubMed  Google Scholar 

  12. 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 28:1347–1354

    Article  CAS  PubMed  Google Scholar 

  13. 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 11:1249–1263

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  14. 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 11:2607–2619

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  15. Lambeth JD, Krause KH, Clark RA (2008) NOX enzymes as novel targets for drug development. Semin Immunopathol 30:339–363

    Article  CAS  PubMed  Google Scholar 

  16. 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 327:717–720

    Article  CAS  PubMed  Google Scholar 

  17. 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 353:312–321

    Article  CAS  PubMed  Google Scholar 

  18. Gao HM, Zhou H, Hong JS (2012) NADPH oxidases: novel therapeutic targets for neurodegenerative diseases. Trends Pharmacol Sci 33:295–303

    Article  PubMed Central  PubMed  Google Scholar 

  19. Babior BM (1978) Oxygen-dependent microbial killing by phagocytes (first of two parts). N Engl J Med 298:659–668

    Article  CAS  PubMed  Google Scholar 

  20. 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 3:24

    Article  Google Scholar 

  21. Heyworth PG, Cross AR, Curnutte JT (2003) Chronic granulomatous disease. Curr Opin Immunol 2003(15):578–584

    Article  Google Scholar 

  22. Appel SH, Beers DR, Henkel JS (2010) T cell-microglial dialogue in Parkinson’s disease and amyotrophic lateral sclerosis: are we listening? Trends Immunol 31:7–17

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  23. Hald A, Van Beek J, Lotharius J (2007) Inflammation in Parkinson’s disease: causative or epiphenomenal? Subcell Biochem 42:249–279

    Article  PubMed  Google Scholar 

  24. Mosher KI, Wyss-Coray T (2014) Microglial dysfunction in brain aging and Alzheimer’s disease. Biochem Pharmacol. doi:10.1016/j.bcp.2014.01.008

    PubMed Central  PubMed  Google Scholar 

  25. 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

    Google Scholar 

  26. Chiò A, Logroscino G, Hardiman O et al (2009) Prognostic factors in ALS: a critical review. Amyotroph Lateral Scler 10:310–323

    Article  PubMed Central  PubMed  Google Scholar 

  27. Kabashi E, Valdmanis PN, Dion P, Rouleau GA (2007) Oxidized/misfolded superoxide dismutase-1: the cause of all amyotrophic lateral sclerosis? Ann Neurol 62:553–559

    Article  CAS  PubMed  Google Scholar 

  28. 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:e75916

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  29. Synofzik M, Ronchi D, Keskin I et al (2012) Mutant superoxide dismutase-1 indistinguishable from wild-type causes ALS. Hum Mol Genet 21:3568–3574

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

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.

Ethical standard

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.

Author information

Authors and Affiliations

  1. “Rita Levi Montalcini” Department of Neuroscience, ALS Centre, University of Torino, Via Cherasco 15, 10126, Turin, Italy

    Giuseppe Marrali, Federico Casale, Paolina Salamone, Giuseppe Fuda, Davide Bertuzzo, Antonio Canosa, Cristina Moglia, Andrea Calvo & Adriano Chiò

  2. Immunogenetics and Transplant Biology Laboratory, Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino, Turin, Italy

    Cristiana Caorsi & Antonio Amoroso

  3. Department of Medical Sciences, University of Torino, Turin, Italy

    Cristiana Caorsi & Antonio Amoroso

  4. Laboratory of Molecular Genetics, Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino, Turin, Italy

    Maura Brunetti, Gabriella Restagno & Marco Barberis

  5. Neurologia 2, Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino, Turin, Italy

    Andrea Calvo & Adriano Chiò

  6. Neuroscience Institute of Torino, Turin, Italy

    Andrea Calvo & Adriano Chiò

Authors
  1. Giuseppe Marrali
    View author publications

    You can also search for this author inPubMed Google Scholar

  2. Federico Casale
    View author publications

    You can also search for this author inPubMed Google Scholar

  3. Paolina Salamone
    View author publications

    You can also search for this author inPubMed Google Scholar

  4. Giuseppe Fuda
    View author publications

    You can also search for this author inPubMed Google Scholar

  5. Cristiana Caorsi
    View author publications

    You can also search for this author inPubMed Google Scholar

  6. Antonio Amoroso
    View author publications

    You can also search for this author inPubMed Google Scholar

  7. Maura Brunetti
    View author publications

    You can also search for this author inPubMed Google Scholar

  8. Gabriella Restagno
    View author publications

    You can also search for this author inPubMed Google Scholar

  9. Marco Barberis
    View author publications

    You can also search for this author inPubMed Google Scholar

  10. Davide Bertuzzo
    View author publications

    You can also search for this author inPubMed Google Scholar

  11. Antonio Canosa
    View author publications

    You can also search for this author inPubMed Google Scholar

  12. Cristina Moglia
    View author publications

    You can also search for this author inPubMed Google Scholar

  13. Andrea Calvo
    View author publications

    You can also search for this author inPubMed Google Scholar

  14. Adriano Chiò
    View author publications

    You can also search for this author inPubMed Google Scholar

Corresponding author

Correspondence to Adriano Chiò.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 88 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Marrali, G., Casale, F., Salamone, P. et al. NADPH oxidase (NOX2) activity is a modifier of survival in ALS. J Neurol 261, 2178–2183 (2014). https://doi.org/10.1007/s00415-014-7470-0

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00415-014-7470-0

Keywords

Profiles

  1. Andrea Calvo View author profile