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Glutathione peroxidase 4: a new player in neurodegeneration?

Molecular Psychiatry volume 22, pages 328–335 (2017)Cite this article

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Abstract

Glutathione peroxidase 4 (GPx4) is an antioxidant enzyme reported as an inhibitor of ferroptosis, a recently discovered non-apoptotic form of cell death. This pathway was initially described in cancer cells and has since been identified in hippocampal and renal cells. In this Perspective, we propose that inhibition of ferroptosis by GPx4 provides protective mechanisms against neurodegeneration. In addition, we suggest that selenium deficiency enhances susceptibility to ferroptotic processes, as well as other programmed cell death pathways due to a reduction in GPx4 activity. We review recent studies of GPx4 with an emphasis on neuronal protection, and discuss the relevance of selenium levels on its enzymatic activity.

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References

  1. Kryukov GV, Castellano S, Novoselov SV, Lobanov AV, Zehtab O, Guigo R et al. Characterization of mammalian selenoproteomes. Science 2003; 300: 1439–1443.

    Article  CAS  PubMed  Google Scholar 

  2. Brigelius-Flohé R, Maiorino M . Glutathione peroxidases. Biochim Biophys Acta 2013; 1830: 3289–3303.

    Article  CAS  PubMed  Google Scholar 

  3. Zhang S, Rocourt C, Cheng W-H . Selenoproteins and the aging brain. Mech Ageing Dev 2010; 131: 253–260.

    Article  CAS  PubMed  Google Scholar 

  4. Wang G, Wu Y, Zhou T, Guo Y, Zheng B, Wang J et al. Mapping of the N-linked glycoproteome of human spermatozoa. J Proteome Res 2013; 12: 5750–5759.

    Article  CAS  PubMed  Google Scholar 

  5. Pitts MW, Byrns CN, Ogawa-Wong AN, Kremer P, Berry MJ . Selenoproteins in nervous system development and function. Biol Trace Elem Res 2014; 161: 231–245.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Dixon SJ, Lemberg KM, Lamprecht MR, Skouta R, Zaitsev EM, Gleason CE et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell 2012; 149: 1060–1072.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Ingold I, Aichler M, Yefremova E, Roveri A, Buday K, Doll S et al. Expression of a catalytically inactive mutant form of glutathione peroxidase 4 (Gpx4) confers a dominant-negative effect in male fertility. J Biol Chem 2015; 290: 14668–14678.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Tosatto SC, Bosello V, Fogolari F, Mauri P, Roveri A, Toppo S et al. The catalytic site of glutathione peroxidases. Antioxid Redox Signal 2008; 10: 1515–1526.

    Article  CAS  PubMed  Google Scholar 

  9. Pfeifer H, Conrad M, Roethlein D, Kyriakopoulos A, Brielmeier M, Bornkamm GW et al. Identification of a specific sperm nuclei selenoenzyme necessary for protamine thiol cross-linking during sperm maturation. FASEB J 2001; 15: 1236–1238.

    Article  CAS  PubMed  Google Scholar 

  10. Casanas-Sanchez V, Perez JA, Fabelo N, Herrera-Herrera AV, Fernandez C, Marin R et al. Addition of docosahexaenoic acid, but not arachidonic acid, activates glutathione and thioredoxin antioxidant systems in murine hippocampal HT22 cells: potential implications in neuroprotection. J Neurochem 2014; 131: 470–483.

    Article  CAS  PubMed  Google Scholar 

  11. Januel C, El Hentati FZ, Carreras M, Arthur JR, Calzada C, Lagarde M et al. Phospholipid-hydroperoxide glutathione peroxidase (GPx-4) localization in resting platelets, and compartmental change during platelet activation. Biochim Biophys Acta 2006; 1761: 1228–1234.

    Article  CAS  PubMed  Google Scholar 

  12. Kelner MJ, Montoya MA . Structural organization of the human selenium-dependent phospholipid hydroperoxide glutathione peroxidase gene (GPX4): chromosomal localization to 19p13.3. Biochem Biophys Res Commun 1998; 249: 53–55.

    Article  CAS  PubMed  Google Scholar 

  13. Gawryluk JW, Wang JF, Andreazza AC, Shao L, Young LT . Decreased levels of glutathione, the major brain antioxidant, in post-mortem prefrontal cortex from patients with psychiatric disorders. Int J Neuropsychopharmacol 2011; 14: 123–130.

    Article  CAS  PubMed  Google Scholar 

  14. Mandal PK, Saharan S, Tripathi M, Murari G . Brain glutathione levels - a novel biomarker for mild cognitive impairment and Alzheimer's disease. Biol Psychiatry 2015; 78: 702–710.

    Article  CAS  PubMed  Google Scholar 

  15. Baker LM, Poole LB . Catalytic mechanism of thiol peroxidase from Escherichia coli. Sulfenic acid formation and overoxidation of essential CYS61. J Biol Chem 2003; 278: 9203–9211.

    Article  CAS  PubMed  Google Scholar 

  16. Wood ZA, Poole LB, Karplus PA . Peroxiredoxin evolution and the regulation of hydrogen peroxide signaling. Science 2003; 300: 650–653.

    Article  CAS  PubMed  Google Scholar 

  17. Imai H, Hirao F, Sakamoto T, Sekine K, Mizukura Y, Saito M et al. Early embryonic lethality caused by targeted disruption of the mouse PHGPx gene. Biochem Biophys Res Commun 2003; 305: 278–286.

    Article  CAS  PubMed  Google Scholar 

  18. Schneider M, Forster H, Boersma A, Seiler A, Wehnes H, Sinowatz F et al. Mitochondrial glutathione peroxidase 4 disruption causes male infertility. Faseb j 2009; 23: 3233–3242.

    Article  CAS  PubMed  Google Scholar 

  19. Puglisi R, Tramer F, Panfili E, Micali F, Sandri G, Boitani C . Differential splicing of the phospholipid hydroperoxide glutathione peroxidase gene in diploid and haploid male germ cells in the rat. Biol Reprod 2003; 68: 405–411.

    Article  CAS  PubMed  Google Scholar 

  20. Puglisi R, Maccari I, Pipolo S, Conrad M, Mangia F, Boitani C . The nuclear form of glutathione peroxidase 4 is associated with sperm nuclear matrix and is required for proper paternal chromatin decondensation at fertilization. J Cell Physiol 2012; 227: 1420–1427.

    Article  CAS  PubMed  Google Scholar 

  21. Arai M, Imai H, Koumura T, Yoshida M, Emoto K, Umeda M et al. Mitochondrial phospholipid hydroperoxide glutathione peroxidase plays a major role in preventing oxidative injury to cells. J Biol Chem 1999; 274: 4924–4933.

    Article  CAS  PubMed  Google Scholar 

  22. Seiler A, Schneider M, Forster H, Roth S, Wirth EK, Culmsee C et al. Glutathione peroxidase 4 senses and translates oxidative stress into 12/15-lipoxygenase dependent- and AIF-mediated cell death. Cell Metab 2008; 8: 237–248.

    Article  CAS  PubMed  Google Scholar 

  23. Yoo SE, Chen L, Na R, Liu Y, Rios C, Van Remmen H et al. Gpx4 ablation in adult mice results in a lethal phenotype accompanied by neuronal loss in brain. Free Radic Biol Med 2012; 52: 1820–1827.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Markesbery WR, Lovell MA . Four-hydroxynonenal, a product of lipid peroxidation, is increased in the brain in Alzheimer's disease. Neurobiol Aging 1998; 19: 33–36.

    Article  CAS  PubMed  Google Scholar 

  25. Williams TI, Lynn BC, Markesbery WR, Lovell MA . Increased levels of 4-hydroxynonenal and acrolein, neurotoxic markers of lipid peroxidation, in the brain in Mild Cognitive Impairment and early Alzheimer's disease. Neurobiol Aging 2006; 27: 1094–1099.

    Article  CAS  PubMed  Google Scholar 

  26. Lopez N, Tormo C, De Blas I, Llinares I, Alom J . Oxidative stress in Alzheimer's disease and mild cognitive impairment with high sensitivity and specificity. J Alzheimers Dis 2013; 33: 823–829.

    Article  CAS  PubMed  Google Scholar 

  27. Tsujii S, Ishisaka M, Shimazawa M, Hashizume T, Hara H . Zonisamide suppresses endoplasmic reticulum stress-induced neuronal cell damage in vitro and in vivo. Eur J Pharmacol 2015; 746: 301–307.

    Article  CAS  PubMed  Google Scholar 

  28. Yoritaka A, Hattori N, Uchida K, Tanaka M, Stadtman ER, Mizuno Y . Immunohistochemical detection of 4-hydroxynonenal protein adducts in Parkinson disease. Proc Natl Acad Sci U S A 1996; 93: 2696–2701.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Karlik M, Valkovic P, Hancinova V, Krizova L, Tothova L, Celec P . Markers of oxidative stress in plasma and saliva in patients with multiple sclerosis. Clin Biochem 2015; 48: 24–28.

    Article  CAS  PubMed  Google Scholar 

  30. Aydin O, Ellidag HY, Eren E, Kurtulus F, Yaman A, Yilmaz N . Ischemia modified albumin is an indicator of oxidative stress in multiple sclerosis. Biochem Med (Zagreb) 2014; 24: 383–389.

    Article  Google Scholar 

  31. Mitsumoto H, Santella RM, Liu X, Bogdanov M, Zipprich J, Wu HC et al. Oxidative stress biomarkers in sporadic ALS. Amyotroph Lateral Scler 2008; 9: 177–183.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Simpson EP, Henry YK, Henkel JS, Smith RG, Appel SH . Increased lipid peroxidation in sera of ALS patients: a potential biomarker of disease burden. Neurology 2004; 62: 1758–1765.

    Article  CAS  PubMed  Google Scholar 

  33. Belanger M, Allaman I, Magistretti PJ . Brain energy metabolism: focus on astrocyte-neuron metabolic cooperation. Cell Metab 2011; 14: 724–738.

    Article  CAS  PubMed  Google Scholar 

  34. Savaskan NE, Borchert A, Brauer AU, Kuhn H . Role for glutathione peroxidase-4 in brain development and neuronal apoptosis: specific induction of enzyme expression in reactive astrocytes following brain injury. Free Radic Biol Med 2007; 43: 191–201.

    Article  CAS  PubMed  Google Scholar 

  35. Perluigi M, Sultana R, Cenini G, Di Domenico F, Memo M, Pierce WM et al. Redox proteomics identification of 4-hydroxynonenal-modified brain proteins in Alzheimer's disease: Role of lipid peroxidation in Alzheimer's disease pathogenesis. Proteomics Clin Appl 2009; 3: 682–693.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Williamson KS, Gabbita SP, Mou S, West M, Pye QN, Markesbery WR et al. The nitration product 5-nitro-gamma-tocopherol is increased in the Alzheimer brain. Nitric Oxide 2002; 6: 221–227.

    Article  CAS  PubMed  Google Scholar 

  37. Hall ED, Detloff MR, Johnson K, Kupina NC . Peroxynitrite-mediated protein nitration and lipid peroxidation in a mouse model of traumatic brain injury. J Neurotrauma 2004; 21: 9–20.

    Article  PubMed  Google Scholar 

  38. Pizzimenti S, Ciamporcero E, Daga M, Pettazzoni P, Arcaro A, Cetrangolo G et al. Interaction of aldehydes derived from lipid peroxidation and membrane proteins. Front Physiol 2013; 4: 242.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Nomura K, Imai H, Koumura T, Kobayashi T, Nakagawa Y . Mitochondrial phospholipid hydroperoxide glutathione peroxidase inhibits the release of cytochrome c from mitochondria by suppressing the peroxidation of cardiolipin in hypoglycaemia-induced apoptosis. Biochem J 2000; 351: 183–193.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Liang H, Van Remmen H, Frohlich V, Lechleiter J, Richardson A, Ran Q . Gpx4 protects mitochondrial ATP generation against oxidative damage. Biochem Biophys Res Commun 2007; 356: 893–898.

    Article  CAS  PubMed  Google Scholar 

  41. Chen L, Na R, Gu M, Richardson A, Ran Q . Lipid peroxidation up-regulates BACE1 expression in vivo: a possible early event of amyloidogenesis in Alzheimer's disease. J Neurochem 2008; 107: 197–207.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Hauser DN, Dukes AA, Mortimer AD, Hastings TG . Dopamine quinone modifies and decreases the abundance of the mitochondrial selenoprotein glutathione peroxidase 4. Free Radic Biol Med 2013; 65: 419–427.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Kim GH, Kim JE, Rhie SJ, Yoon S . The role of oxidative stress in neurodegenerative diseases. Exp Neurobiol 2015; 24: 325–340.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Uttara B, Singh AV, Zamboni P, Mahajan RT . Oxidative stress and neurodegenerative diseases: a review of upstream and downstream antioxidant therapeutic options. Curr Neuropharmacol 2009; 7: 65–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Roberts BR, Ryan TM, Bush AI, Masters CL, Duce JA . The role of metallobiology and amyloid-β peptides in Alzheimer’s disease. J Neurochem 2011; 120: 149–166.

    Article  CAS  PubMed  Google Scholar 

  46. Ayala A, Munoz MF, Arguelles S . Lipid peroxidation: production, metabolism, and signaling mechanisms of malondialdehyde and 4-hydroxy-2-nonenal. Oxid Med Cell Longev 2014; 2014: 360438.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Loscalzo J . Membrane redox state and apoptosis: death by peroxide. Cell Metab 2008; 8: 182–183.

    Article  CAS  PubMed  Google Scholar 

  48. Beal MF . Oxidatively modified proteins in aging and disease. Free Rad Biol Med 2002; 32: 797–803.

    Article  CAS  PubMed  Google Scholar 

  49. Beckman JS . Nitric oxide, superoxide, and peroxynitrite in CNS injury. In: Caplan LR, Siesjo BK, Weir B, Welch KM, Reis DJ (eds). Primer on Cerebrovascular Diseases. Academic Press: Cambridge, UK, 1997 pp 209–210.

    Book  Google Scholar 

  50. Beckman JS, Beckman TW, Chen J, Marshall PA, Freeman BA . Apparent hydroxyl radical production by peroxynitrite: implications for endothelial injury from nitric oxide and superoxide. Proc Natl Acad Sci USA 1990; 87: 1620–1624.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Storkey C, Pattison DI, Ignasiak MT, Schiesser CH, Davies MJ . Kinetics of reaction of peroxynitrite with selenium- and sulfur-containing compounds: Absolute rate constants and assessment of biological significance. Free Radic Biol Med 2015; 89: 1049–1056.

    Article  CAS  PubMed  Google Scholar 

  52. Arteel GE, Mostert V, Oubrahim H, Briviba K, Abel J, Sies H . Protection by selenoprotein P in human plasma against peroxynitrite-mediated oxidation and nitration. Biol Chem 1998; 379: 1201–1205.

    CAS  PubMed  Google Scholar 

  53. Cardoso BR, Roberts BR, Bush AI, Hare DJ . Selenium, selenoproteins and neurodegenerative diseases. Metallomics 2015; 7: 1213–1228.

    Article  CAS  PubMed  Google Scholar 

  54. Arteel GE, Briviba K, Sies H . Function of thioredoxin reductase as a peroxynitrite reductase using selenocystine or ebselen. Chem Res Toxicol 1999; 12: 264–269.

    Article  CAS  PubMed  Google Scholar 

  55. Sies H, Klotz L-O, Sharov VS, Assmann A, Briviba K . Protection against Peroxynitrite by Selenoproteins. Z Naturforsch C 1998; 53: 228–232.

    Article  CAS  PubMed  Google Scholar 

  56. Kade IJ, Balogun BD, Rocha JB . In vitro glutathione peroxidase mimicry of ebselen is linked to its oxidation of critical thiols on key cerebral suphydryl proteins - A novel component of its GPx-mimic antioxidant mechanism emerging from its thiol-modulated toxicology and pharmacology. Chem Biol Interact 2013; 206: 27–36.

    Article  CAS  PubMed  Google Scholar 

  57. Li J, Chen JJ, Zhang F, Zhang C . Ebselen protection against hydrogen peroxide-induced cytotoxicity and DNA damage in HL-60 cells. Acta Pharmacol Sin 2000; 21: 455–459.

    CAS  PubMed  Google Scholar 

  58. Saccoccia F, Angelucci F, Boumis G, Desiato G, Miele AE, Bellelli A . Selenocysteine robustness versus cysteine versatility: a hypothesis on the evolution of the moonlighting behaviour of peroxiredoxins. Biochem Soc Trans 2014; 42: 1768–1772.

    Article  CAS  PubMed  Google Scholar 

  59. Sies H, Sharov VS, Klotz LO, Briviba K . Glutathione peroxidase protects against peroxynitrite-mediated oxidations. A new function for selenoproteins as peroxynitrite reductase. J Biol Chem 1997; 272: 27812–27817.

    Article  CAS  PubMed  Google Scholar 

  60. Briviba K, Kissner R, Koppenol WH, Sies H . Kinetic study of the reaction of glutathione peroxidase with peroxynitrite. Chem Res Toxicol 1998; 11: 1398–1401.

    Article  CAS  PubMed  Google Scholar 

  61. Prabhakar R, Morokuma K, Musaev DG . Peroxynitrite reductase activity of selenoprotein glutathione peroxidase: a computational study. Biochemistry 2006; 45: 6967–6977.

    Article  CAS  PubMed  Google Scholar 

  62. Xu X-M, Turanov AA, Carlson BA, Yoo M-H, Everley RA, Nandakumar R et al. Targeted insertion of cysteine by decoding UGA codons with mammalian selenocysteine machinery. Proc Natl Acad Sci USA 2010; 107: 21430–21434.

    Article  PubMed  PubMed Central  Google Scholar 

  63. Fomenko DE, Marino SM, Gladyshev VN . Functional diversity of cysteine residues in proteins and unique features of catalytic redox-active cysteines in thiol oxidoreductases. Mol Cells 2008; 26: 228–235.

    CAS  PubMed  Google Scholar 

  64. Yu Y, Song J, Guo X, Wang S, Yang X, Chen L et al. Characterization and structural analysis of human selenium-dependent glutathione peroxidase 4 mutant expressed in Escherichia coli. Free Radic Biol Med 2014; 71: 332–338.

    Article  CAS  PubMed  Google Scholar 

  65. Huber RE, Criddle RS . Comparison of the chemical properties of selenocysteine and selenocystine with their sulfur analogs. Arch Biochem Biophys 1967; 122: 164–173.

    Article  CAS  PubMed  Google Scholar 

  66. Mobli M, Morgenstern D, King GF, Alewood PF, Muttenthaler M . Site-specific pka determination of selenocysteine residues in selenovasopressin by using 77Se NMR spectroscopy. Angew Chem Internat Ed 2011; 50: 11952–11955.

    Article  CAS  Google Scholar 

  67. Grauschopf U, Winther JR, Korber P, Zander T, Dallinger P, Bardwell JC . Why is DsbA such an oxidizing disulfide catalyst? Cell 1995; 83: 947–955.

    Article  CAS  PubMed  Google Scholar 

  68. Nelson JW, Creighton TE . Reactivity and ionization of the active site cysteine residues of DsbA, a protein required for disulfide bond formation in vivo. Biochemistry 1994; 33: 5974–5983.

    Article  CAS  PubMed  Google Scholar 

  69. Mannes AM, Seiler A, Bosello V, Maiorino M, Conrad M . Cysteine mutant of mammalian GPx4 rescues cell death induced by disruption of the wild-type selenoenzyme. FASEB J 2011; 25: 2135–2144.

    Article  CAS  PubMed  Google Scholar 

  70. Carlson BA, Tobe R, Yefremova E, Tsuji PA, Hoffmann VJ, Schweizer U et al. Glutathione peroxidase 4 and vitamin E cooperatively prevent hepatocellular degeneration. Redox Biol 2016; 9: 22–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Barayuga SM, Pang X, Andres MA, Panee J, Bellinger FP . Methamphetamine decreases levels of glutathione peroxidases 1 and 4 in SH-SY5Y neuronal cells: protective effects of selenium. Neurotoxicology 2013; 37: 240–246.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Song E, Su C, Fu J, Xia X, Yang S, Xiao C et al. Selenium supplementation shows protective effects against patulin-induced brain damage in mice via increases in GSH-related enzyme activity and expression. Life Sci 2014; 109: 37–43.

    Article  CAS  PubMed  Google Scholar 

  73. Turan B, Acan NL, Ulusu NN, Tezcan EF . A comparative study on effect of dietary selenium and vitamin E on some antioxidant enzyme activities of liver and brain tissues. Biol Trace Elem Res 2001; 81: 141–152.

    Article  CAS  PubMed  Google Scholar 

  74. Sinning A, Hubner CA . Minireview: pH and synaptic transmission. FEBS Lett 2013; 587: 1923–1928.

    Article  CAS  PubMed  Google Scholar 

  75. Rita Cardoso B, Silva Bandeira V, Jacob-Filho W, Franciscato Cozzolino SM . Selenium status in elderly: relation to cognitive decline. J Trace Elem Med Biol 2014; 28: 422–426.

    Article  CAS  PubMed  Google Scholar 

  76. Gonzalez-Dominguez R, Garcia-Barrera T, Gomez-Ariza JL . Homeostasis of metals in the progression of Alzheimer's disease. Biometals 2014; 27: 539–549.

    Article  CAS  PubMed  Google Scholar 

  77. Olde Rikkert MG, Verhey FR, Sijben JW, Bouwman FH, Dautzenberg PL, Lansink M et al. Differences in nutritional status between very mild Alzheimer's disease patients and healthy controls. J Alzheimers Dis 2014; 41: 261–271.

    Article  CAS  PubMed  Google Scholar 

  78. Vural H, Demirin H, Kara Y, Eren I, Delibas N . Alterations of plasma magnesium, copper, zinc, iron and selenium concentrations and some related erythrocyte antioxidant enzyme activities in patients with Alzheimer's disease. J Trace Elem Med Biol 2010; 24: 169–173.

    Article  CAS  PubMed  Google Scholar 

  79. Rita Cardoso B, Apolinario D, da Silva Bandeira V, Busse AL, Magaldi RM, Jacob-Filho W et al. Effects of Brazil nut consumption on selenium status and cognitive performance in older adults with mild cognitive impairment: a randomized controlled pilot trial. Eur J Nutr 2015; 55: 107–116.

    Article  CAS  PubMed  Google Scholar 

  80. Bellinger FP, Bellinger MT, Seale LA, Takemoto AS, Raman AV, Miki T et al. Glutathione Peroxidase 4 is associated with Neuromelanin in Substantia Nigra and Dystrophic Axons in Putamen of Parkinson's brain. Mol Neurodegener 2011; 6: 8–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Cominetti C, de Bortoli MC, Garrido AB Jr, Cozzolino SM . Brazilian nut consumption improves selenium status and glutathione peroxidase activity and reduces atherogenic risk in obese women. Nutr Res 2012; 32: 403–407.

    Article  CAS  PubMed  Google Scholar 

  82. Combs GF Jr. . Biomarkers of selenium status. Nutrients 2015; 7: 2209–2236.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Alfthan G, Aro A, Arvilommi H, Huttunen JK . Selenium metabolism and platelet glutathione peroxidase activity in healthy Finnish men: effects of selenium yeast, selenite, and selenate. Am J Clin Nutr 1991; 53: 120–125.

    Article  CAS  PubMed  Google Scholar 

  84. Kühbacher M, Bartel J, Hoppe B, Alber D, Bukalis G, Bräuer AU et al. The brain selenoproteome: priorities in the hierarchy and different levels of selenium homeostasis in the brain of selenium-deficient rats. J Neurochem 2009; 110: 133–142.

    Article  CAS  PubMed  Google Scholar 

  85. Pitts MW, Kremer PM, Hashimoto AC, Torres DJ, Byrns CN, Williams CS et al. Competition between the brain and testes under selenium-compromised conditions: insight into sex differences in selenium metabolism and risk of neurodevelopmental disease. J Neurosci 2015; 35: 15326–15338.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Yang WS, Stockwell BR . Synthetic lethal screening identifies compounds activating iron-dependent, nonapoptotic cell death in oncogenic-RAS-harboring cancer cells. Chem Biol 2008; 15: 234–245.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Friedmann Angeli JP, Schneider M, Proneth B, Tyurina YY, Tyurin VA, Hammond VJ et al. Inactivation of the ferroptosis regulator Gpx4 triggers acute renal failure in mice. Nat Cell Biol 2014; 16: 1180–1191.

    Article  CAS  PubMed  Google Scholar 

  88. Yang WS, SriRamaratnam R, Welsch ME, Shimada K, Skouta R, Viswanathan VS et al. Regulation of ferroptotic cancer cell death by GPX4. Cell 2014; 156: 317–331.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Chen L, Hambright WS, Na R, Ran Q . Ablation of ferroptosis inhibitor glutathione peroxidase 4 in neurons results in rapid motor neuron degeneration and paralysis. J Biol Chem 2015.

  90. Billings JL, Hare DJ, Nurjono M, Volitakis I, Cherny RA, Bush AI et al. Effects of neonatal iron feeding and chronic clioquinol administration on the Parkinsonian Human A53T transgenic mouse. ACS Chem Neurosci 2016; 7: 360–366.

    Article  CAS  PubMed  Google Scholar 

  91. Hare DJ, Double KL . Iron and dopamine: a toxic couple. Brain 2016; 139: 1026–1035.

    Article  PubMed  Google Scholar 

  92. Ayton S, Lei P, Duce JA, Wong BXW, Sedjahtera A, Adlard PA et al. Ceruloplasmin dysfunction and therapeutic potential for Parkinson disease. Ann Neurol 2013; 73: 554–559.

    Article  CAS  PubMed  Google Scholar 

  93. Do Van B, Gouel F, Jonneaux A, Timmerman K, Gelé P, Petrault M et al. Ferroptosis, a newly characterized form of cell death in Parkinson's disease that is regulated by PKC. Neurobiol Dis 2016; 94: 169–178.

    Article  CAS  PubMed  Google Scholar 

  94. Thiry C, Ruttens A, De Temmerman L, Schneider Y-J, Pussemier L . Current knowledge in species-related bioavailability of selenium in food. Food Chem 2012; 130: 767–784.

    Article  CAS  Google Scholar 

  95. Swanson CA, Patterson BH, Levander OA, Veillon C, Taylor PR, Helzlsouer K et al. Human [74Se]selenomethionine metabolism: a kinetic model. Am J Clin Nutr 1991; 54: 917–926.

    Article  CAS  PubMed  Google Scholar 

  96. Monsen ER . Dietary reference intakes for the antioxidant nutrients: vitamin C, vitamin E, selenium, and carotenoids. J Am Diet Assoc 2000; 100: 637–640.

    Article  CAS  PubMed  Google Scholar 

  97. Sharma A, Kaur P, Kumar V, Gill KD . Attenuation of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine induced nigrostriatal toxicity in mice by N-acetyl cysteine. Cell Mol Biol (Noisy-le-grand) 2007; 53: 48–55.

    CAS  Google Scholar 

  98. Grosicka-Maciag E, Kurpios-Piec D, Grzela T, Czeczot H, Skrzycki M, Szumilo M et al. Protective effect of N-acetyl-L-cysteine against disulfiram-induced oxidative stress and apoptosis in V79 cells. Toxicol Appl Pharmacol 2010; 248: 210–216.

    Article  CAS  PubMed  Google Scholar 

  99. Horst A, Kolberg C, Moraes MS, Riffel APK, Finamor IA, Belló-Klein A et al. Effect of N-acetylcysteine on the spinal-cord glutathione system and nitric-oxide metabolites in rats with neuropathic pain. Neurosci Lett 2014; 569: 163–168.

    Article  CAS  PubMed  Google Scholar 

  100. Yoo M-H, Gu X, Xu X-M, Kim JY, Carlson BA, Patterson AD et al. Delineating the role of glutathione peroxidase 4 in protecting cells against lipid hydroperoxide damage and in Alzheimer's disease. Antioxid Redox Signal 2010; 12: 819–827.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Casanas-Sanchez V, Perez JA, Fabelo N, Quinto-Alemany D, Diaz ML . Docosahexaenoic (DHA) modulates phospholipid-hydroperoxide glutathione peroxidase (Gpx4) gene expression to ensure self-protection from oxidative damage in hippocampal cells. Front Physiol 2015; 6: 203.

    Article  PubMed  PubMed Central  Google Scholar 

  102. Ulatowski LM, Manor D . Vitamin E and neurodegeneration. Neurobiol Dis 2015; 84: 78–83.

    Article  CAS  PubMed  Google Scholar 

  103. Hensley K, Benaksas EJ, Bolli R, Comp P, Grammas P, Hamdheydari L et al. New perspectives on vitamin E: gamma-tocopherol and carboxyelthylhydroxychroman metabolites in biology and medicine. Free Radic Biol Med 2004; 36: 1–15.

    Article  CAS  PubMed  Google Scholar 

  104. Morris MC, Schneider JA, Li H, Tangney CC, Nag S, Bennett DA et al. Brain tocopherols related to Alzheimer's disease neuropathology in humans. Alzheimers Dement 2015; 11: 32–39.

    Article  PubMed  Google Scholar 

  105. Lubos E, Loscalzo J, Handy DE . Glutathione peroxidase-1 in health and disease: from molecular mechanisms to therapeutic opportunities. Antioxidants Redox Signal 2011; 15: 1957–1997.

    Article  CAS  Google Scholar 

  106. Florian S, Wingler K, Schmehl K, Jacobasch G, Kreuzer OJ, Meyerhof W et al. Cellular and subcellular localization of gastrointestinal glutathione peroxidase in normal and malignant human intestinal tissue. Free Radic Res 2001; 35: 655–663.

    Article  CAS  PubMed  Google Scholar 

  107. Olson GE, Whitin JC, Hill KE, Winfrey VP, Motley AK, Austin LM et al. Extracellular glutathione peroxidase (Gpx3) binds specifically to basement membranes of mouse renal cortex tubule cells. Am J Physiol 2010; 298: F1244–F1253.

    CAS  Google Scholar 

  108. Gundry RL, Fu Q, Jelinek CA, Van Eyk JE, Cotter RJ . Investigation of an albumin-enriched fraction of human serum and its albuminome. Proteom Clin Appl 2007; 1: 73–88.

    Article  CAS  Google Scholar 

  109. Baek IJ, Seo DS, Yon JM, Lee SR, Jin Y, Nahm SS et al. Tissue expression and cellular localization of phospholipid hydroperoxide glutathione peroxidase (PHGPx) mRNA in male mice. J Mol Histol 2007; 38: 237–244.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

BRC is supported by a Science without Borders (Ciência sem Fronteiras) Fellowship. DJH and BRR receive financial support from the Australian Research Council Linkage Projects scheme (LP140100095). We wish to acknowledge support from the Victorian Government Operational Infrastructure Support Program, and the Cooperative Research Centre for Mental Health.

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Author notes

  1. B R Cardoso and D J Hare: These authors contributed equally to this work.

Authors and Affiliations

  1. The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, VIC, Australia

    B R Cardoso, D J Hare, A I Bush & B R Roberts

  2. Elemental Bio-imaging Facility, University of Technology Sydney, Broadway, NSW, Australia

    D J Hare

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  1. B R Cardoso
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  2. D J Hare
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  3. A I Bush
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  4. B R Roberts
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Corresponding authors

Correspondence to B R Cardoso or B R Roberts.

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Cardoso, B., Hare, D., Bush, A. et al. Glutathione peroxidase 4: a new player in neurodegeneration?. Mol Psychiatry 22, 328–335 (2017). https://doi.org/10.1038/mp.2016.196

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  • DOI: https://doi.org/10.1038/mp.2016.196

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