From Reactive Oxygen and Nitrogen Species to Therapy

Abstract

Excessive free radicals, including reactive oxygen species (ROS) and nitric oxide (NO), contribute to pathological production of misfolded proteins, synaptic damage and apoptosis. Misfolded protein aggregates occur in several chronic neurodegenerative disorders, including Parkinson and Alzheimer diseases. In rare cases, the cause is a genetic mutation; the majority is sporadic and may be a response to environmental factors that generate free radicals. Overactivity of the N‐methyl‐d‐aspartate (NMDA)‐subtype of glutamate receptor can generate ROS and NO species that mediate protein misfolding, synaptic damage and apoptosis, and thus, neurodegenerative disease. We review current evidence that excessive ROS and NO contribute to protein misfolding by S‐nitrosylation of the E3 ubiquitin ligase parkin and protein‐disulfide isomerase. We also discuss NMDA receptor antagonists memantine and NitroMemantine, drugs that block excessive glutamate excitation, thereby limiting production of ROS and NO, and therapeutic electrophiles, drugs that protect cells from oxidative stress by activating the Nrf2 transcriptional pathway.

Key Concepts:

  • S‐nitrosylation or transfer of the NO group to critical cysteine thiol can regulate protein function.

  • Under pathological circumstances, aberrant S‐nitrosylation reactions can contribute to protein misfolding, neuronal injury and neurodegeneration.

Keywords: reactive oxygen species; S‐nitrosylation; molecular chaperone; ubiquitin‐proteasome system; protein misfolding; electrophiles

Figure 1.

Excess activation of the NMDA receptor (NMDAR) by glutamate (Glu) and glycine (Gly) induces Ca2+ influx and activates excitotoxic pathways. NMDAR hyperactivation triggers (1) generation of NO by neuronal NO synthase (nNOS) and (2) production and release of ROS from mitochondria. Additionally, generation of mitochondrial ROS occurs on environmental toxin stimuli or during the normal ageing process. Excessively produced NO and ROS contribute to protein misfolding, neuronal cell injury and death.

Figure 2.

Chemical pathways for nitrogen and oxygen free radical species. Production of ROS by the mitochondrial respiratory chain or certain enzymatic reactions (e.g. NADPH oxidase) can lead to the formation of superoxide anion (O2•−) or other toxic substances such as hydrogen peroxide (H2O2) and hydroxyl radical (OH). A series of antioxidative enzymes, including superoxide dismutase (SOD), catalase and glutathione peroxidase (GPx), decomposes such toxic oxygen radicals to water. When the rate of free radical production exceeds the antioxidative defence mechanisms, oxidative stress occurs. NOS produces NO from l‐arginine, and NO reacts with sulfhydryl groups to form S‐nitrosothiols (R‐SNO). NO activates soluble guanylate cyclase (sGC) to produce cGMP, and cGMP can activate cGMP‐dependent protein kinase. Peroxynitrite (ONOO), derived from a reaction of NO and superoxide anion, can oxidize vicinal sulfhydryl groups to disulfide bonds and can also nitrate tyrosine residues to form 3‐nitrotyrosine (3‐NT). Accumulation of R‐SNO and 3‐NT contributes to nitrosative stress.

Figure 3.

S‐nitrosylation of neuronal proteins. Physiological levels of NO mediate neuroprotective effects, at least in part, by S‐nitrosylating the NMDAR and caspases, thus inhibiting their activity. In contrast, overproduction of NO can be neurotoxic via S‐nitrosylation of Parkin, PDI, GAPDH, MMP‐2/9, PrxII and COX‐2. S‐nitrosylated parkin and PDI contribute to neuronal cell injury by triggering accumulation of misfolded proteins. S‐nitrosylation of Drp1 causes excessive mitochondrial fragmentation in neurodegenerative conditions.

Figure 4.

Possible mechanism whereby S‐nitrosylated species contribute to the accumulation of aberrant proteins and neuronal damage. S‐nitrosylation of parkin (forming SNO‐PARK) and PDI (forming SNO‐PDI) can contribute to neuronal cell injury in part by triggering accumulation of misfolded proteins. Specifically, S‐nitrosylation of parkin disturbs its E3 ligase activity, thus inducing dysfunction in the ubiquitin proteasome system (UPS) (left). S‐nitrosylated PDI decreases its molecular chaperone and disulfide isomerase activity (right).

Figure 5.

S‐nitrosylation and Memantine/NitroMemantine regulate NMDA receptor activity. (a) NO‐induced inhibition of NMDA receptor. Relatively hypoxic conditions (brain oxygen levels are normally low under physiological conditions) render the NMDA receptor exquisitely sensitive to S‐nitrosylation of Cys744 and Cys798 on the NR1 subunit. NO modification of these two thiols in NR1 further enhances S‐nitrosylation of the Cys399 site on the NR2A subunit, resulting in the inhibition of receptor activity by very low levels of NO. Under certain physiological conditions, NR2A can also be nitrosylated at Cys87 and Cys320 (not shown for clarity). (b) Memantine and NitroMemantine preferentially block excessive extrasynaptic NMDA receptor activity. (Left) Normal (physiological/synaptic) activity of the NMDAR is required for synaptic function and neuronal survival. (Middle) Excessive activation of the NMDAR, predominantly at extrasynaptic sites, is thought to induce neuronal cell injury and death, and is associated with the accumulation of misfolded proteins. (Right) Memantine (Mem) and the newer NitroMemantine drugs (NitroMem) preferentially block excessive (pathological) extrasynaptic NMDA receptor activity, whereas relatively sparing normal (physiological) synaptic activity.

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References

Abu‐Soud HM and Stuehr DJ (1993) Nitric oxide synthases reveal a role for calmodulin in controlling electron transfer. Proceedings of the National Academy of Sciences of the USA 90: 10769–10772.

Arrasate M, Mitra S, Schweitzer ES, Segal MR and Finkbeiner S (2004) Inclusion body formation reduces levels of mutant huntingtin and the risk of neuronal death. Nature 431: 805–810.

Aruoma OI, Halliwell B, Aeschbach R and Loligers J (1992) Antioxidant and pro‐oxidant properties of active rosemary constituents: carnosol and carnosic acid. Xenobiotica 22: 257–268.

Auluck PK, Chan HY, Trojanowski JQ, Lee VM and Bonini NM (2002) Chaperone suppression of alpha‐synuclein toxicity in a Drosophila model for Parkinson's disease. Science 295: 865–868.

Beal MF (2001) Experimental models of Parkinson's disease. Nature Reviews. Neuroscience 2: 325–334.

Betarbet R, Sherer TB, MacKenzie G et al. (2000) Chronic systemic pesticide exposure reproduces features of Parkinson's disease. Nature Neuroscience 3: 1301–1306.

Bonfoco E, Krainc D, Ankarcrona M, Nicotera P and Lipton SA (1995) Apoptosis and necrosis: two distinct events induced, respectively, by mild and intense insults with N‐methyl‐d‐aspartate or nitric oxide/superoxide in cortical cell cultures. Proceedings of the National Academy of Sciences of the USA 92: 7162–7166.

Chen HS, Pellegrini JW, Aggarwal SK et al. (1992) Open‐channel block of N‐methyl‐d‐aspartate (NMDA) responses by memantine: therapeutic advantage against NMDA receptor‐mediated neurotoxicity. Journal of Neuroscience 12: 4427–4436.

Cho DH, Nakamura T, Fang J et al. (2009) S‐nitrosylation of Drp1 mediates beta‐amyloid‐related mitochondrial fission and neuronal injury. Science 324: 102–105.

Chung KK, Thomas B, Li X et al. (2004) S‐nitrosylation of parkin regulates ubiquitination and compromises parkin's protective function. Science 304: 1328–1331.

Ciechanover A and Brundin P (2003) The ubiquitin proteasome system in neurodegenerative diseases: sometimes the chicken, sometimes the egg. Neuron 40: 427–446.

Conn KJ, Gao W, McKee A et al. (2004) Identification of the protein disulfide isomerase family member PDIp in experimental Parkinson's disease and Lewy body pathology. Brain Research 1022: 164–172.

Dawson VL, Dawson TM, London ED, Bredt DS and Snyder SH (1991) Nitric oxide mediates glutamate neurotoxicity in primary cortical cultures. Proceedings of the National Academy of Sciences of the USA 88: 6368–6371.

Forrester MT, Benhar M and Stamler JS (2006) Nitrosative stress in the ER: a new role for S‐nitrosylation in neurodegenerative diseases. ACS Chemical Biology 1: 355–358.

Gu Z, Kaul M, Yan B et al. (2002) S‐nitrosylation of matrix metalloproteinases: signaling pathway to neuronal cell death. Science 297: 1186–1190.

Hara MR, Agrawal N, Kim SF et al. (2005) S‐nitrosylated GAPDH initiates apoptotic cell death by nuclear translocation following Siah1 binding. Nature Cell Biology 7: 665–674.

Houk KN, Hietbrink BN, Bartberger MD et al. (2003) Nitroxyl disulfides, novel intermediates in transnitrosation reactions. Journal of American Chemical Society 125: 6972–6976.

Isaacs AM, Senn DB, Yuan M, Shine JP and Yankner BA (2006) Acceleration of amyloid beta‐peptide aggregation by physiological concentrations of calcium. Journal of Biological Chemistry 281: 27916–27923.

Itoh K, Tong KI and Yamamoto M (2004) Molecular mechanism activating Nrf2‐Keap1 pathway in regulation of adaptive response to electrophiles. Free Radical Biology & Medicine 36: 1208–1213.

Jenner P (2007) Oxidative stress and Parkinson's disease. Handbook of Clinical Neurology 83: 507–520.

Kopito RR and Ron D (2000) Conformational disease. Nature Cell Biology 2: E207–209.

Kosaka K and Yokoi T (2003) Carnosic acid, a component of rosemary (Rosmarinus officinalis L.), promotes synthesis of nerve growth factor in T98G human glioblastoma cells. Biological & Pharmaceutical Bulletin 26: 1620–1622.

Kraft AD, Johnson DA and Johnson JA (2004) Nuclear factor E2‐related factor 2‐dependent antioxidant response element activation by tert‐butylhydroquinone and sulforaphane occurring preferentially in astrocytes conditions neurons against oxidative insult. Journal Neuroscience 24: 1101–1112.

Lipton SA, Choi YB, Pan ZH et al. (1993) A redox‐based mechanism for the neuroprotective and neurodestructive effects of nitric oxide and related nitroso‐compounds. Nature 364: 626–632.

Lipton SA, Nakamura T, Yao D et al. (2005) Comment on “S‐nitrosylation of parkin regulates ubiquitination and compromises parkin's protective function”. Science 308: 1870.

Lipton SA and Rosenberg PA (1994) Excitatory amino acids as a final common pathway for neurologic disorders. New England Journal of Medicine 330: 613–622.

Lipton SA (2004) Turning down, but not off. Nature 428: 473.

Lipton SA (2006) Paradigm shift in neuroprotection by NMDA receptor blockade: memantine and beyond. Nature Reviews. Drug Discovery 5: 160–170.

Lipton SA (2007) Pathologically activated therapeutics for neuroprotection. Nature Reviews. Neuroscience 8: 803–808.

Lyles MM and Gilbert HF (1991) Catalysis of the oxidative folding of ribonuclease A by protein disulfide isomerase: dependence of the rate on the composition of the redox buffer. Biochemistry 30: 613–619.

Marin I and Ferrus A (2002) Comparative genomics of the RBR family, including the Parkinson's disease‐related gene parkin and the genes of the ariadne subfamily. Molecular Biology and Evolution 19: 2039–2050.

Mayer ML, Westbrook GL and Guthrie PB (1984) Voltage‐dependent block by Mg2+ of NMDA responses in spinal cord neurones. Nature 309: 261–263.

McNaught KS, Perl DP, Brownell AL and Olanow CW (2004) Systemic exposure to proteasome inhibitors causes a progressive model of Parkinson's disease. Annals of Neurology 56: 149–162.

Murphy TH, Schnaar RL and Coyle JT (1990) Immature cortical neurons are uniquely sensitive to glutamate toxicity by inhibition of cystine uptake. FASEB Journal 4: 1624–1633.

Nakamura Y, Kumagai T, Yoshida C et al. (2003) Pivotal role of electrophilicity in glutathione S‐transferase induction by tert‐butylhydroquinone. Biochemistry 42: 4300–4309.

Olney JW (1969) Brain lesions, obesity, and other disturbances in mice treated with monosodium glutamate. Science 164: 719–721.

Papadia S, Soriano FX, Leveille F et al. (2008) Synaptic NMDA receptor activity boosts intrinsic antioxidant defenses. Nature Neuroscience 11: 476–487.

Paz Gavilan M, Vela J, Castano A et al. (2006) Cellular environment facilitates protein accumulation in aged rat hippocampus. Neurobiology of Aging 27: 973–982.

Ross CA and Pickart CM (2004) The ubiquitin‐proteasome pathway in Parkinson's disease and other neurodegenerative diseases. Trends in Cell Biology 14: 703–711.

Satoh T, Kosaka K, Itoh K et al. (2008) Carnosic acid, a catechol‐type electrophilic compound, protects neurons both in vitro and in vivo through activation of the Keap1/Nrf2 pathway via S‐alkylation of targeted cysteines on Keap1. Journal of Neurochemistry 104: 1116–1131.

Satoh T and Lipton SA (2007) Redox regulation of neuronal survival mediated by electrophilic compounds. Trends in Neuroscience 30: 37–45.

Satoh T, Okamoto SI, Cui J et al. (2006) Activation of the Keap1/Nrf2 pathway for neuroprotection by electrophilic [correction of electrophillic] phase II inducers. Proceedings of the National Academy of Sciences of the USA 103: 768–773.

Shibata T, Iio K, Kawai Y et al. (2006) Identification of a lipid peroxidation product as a potential trigger of the p53 pathway. Journal of Biological Chemistry 281: 1196–1204.

Spencer JP, Jenner A, Aruoma OI et al. (1994) Intense oxidative DNA damage promoted by L‐dopa and its metabolites. Implications for neurodegenerative disease. FEBS Letters 24: 246–250.

Stamler JS, Lamas S and Fang FC (2001) Nitrosylation. The prototypic redox‐based signaling mechanism. Cell 106: 675–683.

Uehara T, Nakamura T, Yao D et al. (2006) S‐nitrosylated protein‐disulphide isomerase links protein misfolding to neurodegeneration. Nature 441: 513–517.

Xu L, Eu JP, Meissner G and Stamler JS (1998) Activation of the cardiac calcium release channel (ryanodine receptor) by poly S‐nitrosylation. Science 279: 234–237.

Yao D, Gu Z, Nakamura T et al. (2004) Nitrosative stress linked to sporadic Parkinson's disease: S‐nitrosylation of parkin regulates its E3 ubiquitin ligase activity. Proceedings of the National Academy of Sciences of the USA 101: 10810–10814.

Yazawa K, Kihara T, Shen H et al. (2006) Distinct mechanisms underlie distinct polyphenol‐induced neuroprotection. FEBS Letters 580: 6623–6628.

Zhang K and Kaufman RJ (2006) The unfolded protein response: a stress signaling pathway critical for health and disease. Neurology 66: S102–109.

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McKercher, Scott R, Nakamura, Tomohiro, and Lipton, Stuart A(Dec 2009) From Reactive Oxygen and Nitrogen Species to Therapy. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0021989]