, Volume 15, Issue 11, pp 1364–1370

Modulation of pro-survival proteins by S-nitrosylation: implications for neurodegeneration

Apoptosis in the aging brain


Nitric oxide (NO) is a gaseous signaling molecule in the biological system. It mediates its function through the direct modification of various cellular targets, such as through S-nitrosylation. The process of S-nitrosylation involves the attachment of NO to the cysteine residues of proteins. Interestingly, an increasing number of cellular pathways are found to be regulated by S-nitrosylation, and it has been proposed that this redox signaling pathway is comparable to phosphorylation in cells. However, imbalance of NO metabolism has also been linked to a number of human diseases. For instance, NO is known to contribute to neurodegeneration by causing protein nitration, lipid peroxidation and DNA damage. Moreover, recent studies show that NO can also contribute to the process of neurodegeneration through the impairment of pro-survival proteins by S-nitroyslation. Thus, further understanding of how NO, through S-nitrosylation, can compromise neuronal survival will provide potential therapeutic targets for neurodegenerative diseases.


Nitric oxide Protein misfolding Oxidative stress Programmed cell death Mitochondrial dysfunction Ubiquitin 


  1. 1.
    Tsang AH, Chung KK (2009) Oxidative and nitrosative stress in Parkinson’s disease. Biochim Biophys Acta 1792:643–650PubMedGoogle Scholar
  2. 2.
    Duda JE, Giasson BI, Chen Q et al (2000) Widespread nitration of pathological inclusions in neurodegenerative synucleinopathies. Am J Pathol 157:1439–1445PubMedGoogle Scholar
  3. 3.
    Giasson BI, Duda JE, Murray IV et al (2000) Oxidative damage linked to neurodegeneration by selective alpha-synuclein nitration in synucleinopathy lesions. Science 290:985–989CrossRefPubMedGoogle Scholar
  4. 4.
    Horiguchi T, Uryu K, Giasson BI et al (2003) Nitration of tau protein is linked to neurodegeneration in tauopathies. Am J Pathol 163:1021–1031PubMedGoogle Scholar
  5. 5.
    Reynolds MF, Burstyn JN (2000) Mechanism of activation of soluble guanylyl cyclase by NO. In: Ignarro L (ed) Nitric oxide biology and pathobiology. Academic Press, San Diego, pp 57–82Google Scholar
  6. 6.
    Martinez-Ruiz A, Lamas S (2004) S-nitrosylation: a potential new paradigm in signal transduction. Cardiovasc Res 62:43–52CrossRefPubMedGoogle Scholar
  7. 7.
    Gaston B (1999) Nitric oxide and thiol groups. Biochim Biophys Acta 1411:323–333CrossRefPubMedGoogle Scholar
  8. 8.
    Lipton AJ, Johnson MA, Macdonald T, Lieberman MW, Gozal D, Gaston B (2001) S-nitrosothiols signal the ventilatory response to hypoxia. Nature 413:171–174CrossRefPubMedGoogle Scholar
  9. 9.
    Liu L, Hausladen A, Zeng M, Que L, Heitman J, Stamler JS (2001) A metabolic enzyme for S-nitrosothiol conserved from bacteria to humans. Nature 410:490–494CrossRefPubMedGoogle Scholar
  10. 10.
    Liu L, Yan Y, Zeng M et al (2004) Essential roles of S-nitrosothiols in vascular homeostasis and endotoxic shock. Cell 116:617–628CrossRefPubMedGoogle Scholar
  11. 11.
    Garban HJ, Marquez-Garban DC, Pietras RJ, Ignarro LJ (2005) Rapid nitric oxide-mediated S-nitrosylation of estrogen receptor: regulation of estrogen-dependent gene transcription. Proc Natl Acad Sci USA 102:2632–2636CrossRefPubMedGoogle Scholar
  12. 12.
    Marshall HE, Hess DT, Stamler JS (2004) S-nitrosylation: physiological regulation of NF-kappaB. Proc Natl Acad Sci USA 101:8841–8842CrossRefPubMedGoogle Scholar
  13. 13.
    Reynaert NL, Ckless K, Korn SH et al (2004) Nitric oxide represses inhibitory kappaB kinase through S-nitrosylation. Proc Natl Acad Sci USA 101:8945–8950CrossRefPubMedGoogle Scholar
  14. 14.
    Kaelin WG Jr (2005) The von Hippel-Lindau protein, HIF hydroxylation, and oxygen sensing. Biochem Biophys Res Commun 338:627–638CrossRefPubMedGoogle Scholar
  15. 15.
    Riccio A, Alvania RS, Lonze BE et al (2006) A nitric oxide signaling pathway controls CREB-mediated gene expression in neurons. Mol Cell 21:283–294CrossRefPubMedGoogle Scholar
  16. 16.
    Li F, Sonveaux P, Rabbani ZN et al (2007) Regulation of HIF-1alpha stability through S-nitrosylation. Mol Cell 26:63–74CrossRefPubMedGoogle Scholar
  17. 17.
    Nott A, Watson PM, Robinson JD, Crepaldi L, Riccio A (2008) S-Nitrosylation of histone deacetylase 2 induces chromatin remodelling in neurons. Nature 455:411–415CrossRefPubMedGoogle Scholar
  18. 18.
    Eu JP, Sun J, Xu L, Stamler JS, Meissner G (2000) The skeletal muscle calcium release channel: coupled O2 sensor and NO signaling functions. Cell 102:499–509CrossRefPubMedGoogle Scholar
  19. 19.
    Sun J, Xu L, Eu JP, Stamler JS, Meissner G (2001) Classes of thiols that influence the activity of the skeletal muscle calcium release channel. J Biol Chem 276:15625–15630CrossRefPubMedGoogle Scholar
  20. 20.
    Choi YB, Tenneti L, Le DA et al (2000) Molecular basis of NMDA receptor-coupled ion channel modulation by S-nitrosylation. Nat Neurosci 3:15–21CrossRefPubMedGoogle Scholar
  21. 21.
    Lipton SA, Choi YB, Takahashi H et al (2002) Cysteine regulation of protein function—as exemplified by NMDA-receptor modulation. Trends Neurosci 25:474–480CrossRefPubMedGoogle Scholar
  22. 22.
    Whalen EJ, Foster MW, Matsumoto A et al (2007) Regulation of beta-adrenergic receptor signaling by S-nitrosylation of G-protein-coupled receptor kinase 2. Cell 129:511–522CrossRefPubMedGoogle Scholar
  23. 23.
    Ozawa K, Whalen EJ, Nelson CD et al (2008) S-nitrosylation of beta-arrestin regulates beta-adrenergic receptor trafficking. Mol Cell 31:395–405CrossRefPubMedGoogle Scholar
  24. 24.
    Matsushita K, Morrell CN, Cambien B et al (2003) Nitric oxide regulates exocytosis by S-nitrosylation of N-ethylmaleimide-sensitive factor. Cell 115:139–150CrossRefPubMedGoogle Scholar
  25. 25.
    Wang G, Moniri NH, Ozawa K, Stamler JS, Daaka Y (2006) Nitric oxide regulates endocytosis by S-nitrosylation of dynamin. Proc Natl Acad Sci USA 103:1295–1300CrossRefPubMedGoogle Scholar
  26. 26.
    Huang Y, Man HY, Sekine-Aizawa Y et al (2005) S-nitrosylation of N-ethylmaleimide sensitive factor mediates surface expression of AMPA receptors. Neuron 46:533–540CrossRefPubMedGoogle Scholar
  27. 27.
    Bonifacino JS, Glick BS (2004) The mechanisms of vesicle budding and fusion. Cell 116:153–166CrossRefPubMedGoogle Scholar
  28. 28.
    Qian Z, Gelzer-Bell R, Yang Sx SX et al (2001) Inducible nitric oxide synthase inhibition of weibel-palade body release in cardiac transplant rejection. Circulation 104:2369–2375CrossRefPubMedGoogle Scholar
  29. 29.
    Selvakumar B, Huganir RL, Snyder SH (2009) S-nitrosylation of stargazin regulates surface expression of AMPA-glutamate neurotransmitter receptors. Proc Natl Acad Sci USA 106:16440–16445CrossRefPubMedGoogle Scholar
  30. 30.
    Andersen JK (2004) Oxidative stress in neurodegeneration: cause or consequence? Nat Med 10(Suppl):S18–S25CrossRefPubMedGoogle Scholar
  31. 31.
    Barnham KJ, Masters CL, Bush AI (2004) Neurodegenerative diseases and oxidative stress. Nat Rev Drug Discov 3:205–214CrossRefPubMedGoogle Scholar
  32. 32.
    Chung KK, Dawson VL, Dawson TM (2001) The role of the ubiquitin-proteasomal pathway in Parkinson’s disease and other neurodegenerative disorders. Trends Neurosci 24:S7–14CrossRefPubMedGoogle Scholar
  33. 33.
    Beal MF (2002) Oxidatively modified proteins in aging and disease. Free Radic Biol Med 32:797–803CrossRefPubMedGoogle Scholar
  34. 34.
    Law A, Gauthier S, Quirion R (2001) Say NO to Alzheimer’s disease: the putative links between nitric oxide and dementia of the Alzheimer’s type. Brain Res Brain Res Rev 35:73–96CrossRefPubMedGoogle Scholar
  35. 35.
    Haendeler J, Hoffmann J, Tischler V, Berk BC, Zeiher AM, Dimmeler S (2002) Redox regulatory and anti-apoptotic functions of thioredoxin depend on S-nitrosylation at cysteine 69. Nat Cell Biol 4:743–749CrossRefPubMedGoogle Scholar
  36. 36.
    Mannick JB, Hausladen A, Liu L et al (1999) Fas-induced caspase denitrosylation. Science 284:651–654CrossRefPubMedGoogle Scholar
  37. 37.
    Mannick JB, Schonhoff C, Papeta N et al (2001) S-Nitrosylation of mitochondrial caspases. J Cell Biol 154:1111–1116CrossRefPubMedGoogle Scholar
  38. 38.
    Cherfils J, Chardin P (1999) GEFs: structural basis for their activation of small GTP-binding proteins. Trends Biochem Sci 24:306–311CrossRefPubMedGoogle Scholar
  39. 39.
    Williams JG, Pappu K, Campbell SL (2003) Structural and biochemical studies of p21Ras S-nitrosylation and nitric oxide-mediated guanine nucleotide exchange. Proc Natl Acad Sci USA 100:6376–6381CrossRefPubMedGoogle Scholar
  40. 40.
    Hara MR, Agrawal N, Kim SF et al (2005) S-nitrosylated GAPDH initiates apoptotic cell death by nuclear translocation following Siah1 binding. Nat Cell Biol 7:665–674CrossRefPubMedGoogle Scholar
  41. 41.
    Gu Z, Kaul M, Yan B et al (2002) S-nitrosylation of matrix metalloproteinases: signaling pathway to neuronal cell death. Science 297:1186–1190CrossRefPubMedGoogle Scholar
  42. 42.
    Qu D, Rashidian J, Mount MP et al (2007) Role of Cdk5-mediated phosphorylation of Prx2 in MPTP toxicity and Parkinson’s disease. Neuron 55:37–52CrossRefPubMedGoogle Scholar
  43. 43.
    Fang J, Nakamura T, Cho DH, Gu Z, Lipton SA (2007) S-nitrosylation of peroxiredoxin 2 promotes oxidative stress-induced neuronal cell death in Parkinson’s disease. Proc Natl Acad Sci USA 104:18742–18747CrossRefPubMedGoogle Scholar
  44. 44.
    Cho DH, Nakamura T, Fang J et al (2009) S-nitrosylation of Drp1 mediates beta-amyloid-related mitochondrial fission and neuronal injury. Science 324:102–105CrossRefPubMedGoogle Scholar
  45. 45.
    Chan DC (2006) Mitochondria: dynamic organelles in disease, aging, and development. Cell 125:1241–1252CrossRefPubMedGoogle Scholar
  46. 46.
    Chen H, McCaffery JM, Chan DC (2007) Mitochondrial fusion protects against neurodegeneration in the cerebellum. Cell 130:548–562CrossRefPubMedGoogle Scholar
  47. 47.
    Uehara T, Nakamura T, Yao D et al (2006) S-nitrosylated protein-disulphide isomerase links protein misfolding to neurodegeneration. Nature 441:513–517CrossRefPubMedGoogle Scholar
  48. 48.
    Kitada T, Asakawa S, Hattori N et al (1998) Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature 392:605–608CrossRefPubMedGoogle Scholar
  49. 49.
    Dawson TM, Dawson VL (2003) Molecular pathways of neurodegeneration in Parkinson’s disease. Science 302:819–822CrossRefPubMedGoogle Scholar
  50. 50.
    Chung KK, Thomas B, Li X et al (2004) S-nitrosylation of parkin regulates ubiquitination and compromises parkin’s protective function. Science 304:1328–1331CrossRefPubMedGoogle Scholar
  51. 51.
    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. Proc Natl Acad Sci USA 101:10810–10814CrossRefPubMedGoogle Scholar
  52. 52.
    Chung KK, Dawson TM, Dawson VL (2005) Nitric oxide, S-nitrosylation and neurodegeneration. Cell Mol Biol (Noisy-le-grand) 51:247–254Google Scholar
  53. 53.
    Schulz JB (2006) Anti-apoptotic gene therapy in Parkinson’s disease. J Neural Transm 70(Suppl):467–476CrossRefGoogle Scholar
  54. 54.
    Leuner K, Pantel J, Frey C et al (2007) Enhanced apoptosis, oxidative stress and mitochondrial dysfunction in lymphocytes as potential biomarkers for Alzheimer’s disease. J Neural Transm 72(Suppl):207–215CrossRefGoogle Scholar
  55. 55.
    Sen N, Hara MR, Ahmad AS et al (2009) GOSPEL: a neuroprotective protein that binds to GAPDH upon S-nitrosylation. Neuron 63:81–91CrossRefPubMedGoogle Scholar
  56. 56.
    Sen N, Hara MR, Kornberg MD et al (2008) Nitric oxide-induced nuclear GAPDH activates p300/CBP and mediates apoptosis. Nat Cell Biol 10:866–873CrossRefPubMedGoogle Scholar
  57. 57.
    Tsang AH, Lee YI, Ko HS et al (2009) S-nitrosylation of XIAP compromises neuronal survival in Parkinson’s disease. Proc Natl Acad Sci USA 106:4900–4905CrossRefPubMedGoogle Scholar
  58. 58.
    Bae BI, Hara MR, Cascio MB et al (2006) Mutant huntingtin: nuclear translocation and cytotoxicity mediated by GAPDH. Proc Natl Acad Sci USA 103:3405–3409CrossRefPubMedGoogle Scholar
  59. 59.
    Hara MR, Thomas B, Cascio MB et al (2006) Neuroprotection by pharmacologic blockade of the GAPDH death cascade. Proc Natl Acad Sci USA 103:3887–3889CrossRefPubMedGoogle Scholar
  60. 60.
    Vaux DL, Silke J (2005) IAPs, RINGs and ubiquitylation. Nat Rev Mol Cell Biol 6:287–297CrossRefPubMedGoogle Scholar
  61. 61.
    Srinivasula SM, Ashwell JD (2008) IAPs: what’s in a name? Mol Cell 30:123–135CrossRefPubMedGoogle Scholar
  62. 62.
    Eckelman BP, Salvesen GS, Scott FL (2006) Human inhibitor of apoptosis proteins: why XIAP is the black sheep of the family. EMBO Rep 7:988–994CrossRefPubMedGoogle Scholar
  63. 63.
    Crook NE, Clem RJ, Miller LK (1993) An apoptosis-inhibiting baculovirus gene with a zinc finger-like motif. J Virol 67:2168–2174PubMedGoogle Scholar
  64. 64.
    Lu M, Lin SC, Huang Y et al (2007) XIAP induces NF-kappaB activation via the BIR1/TAB 1 interaction and BIR1 dimerization. Mol Cell 26:689–702CrossRefPubMedGoogle Scholar
  65. 65.
    Lim KH, Ancrile BB, Kashatus DF, Counter CM (2008) Tumour maintenance is mediated by eNOS. Nature 452:646–649CrossRefPubMedGoogle Scholar
  66. 66.
    Raines KW, Bonini MG, Campbell SL (2007) Nitric oxide cell signaling: S-nitrosation of Ras superfamily GTPases. Cardiovasc Res 75:229–239CrossRefPubMedGoogle Scholar
  67. 67.
    Zhai D, Jin C, Huang Z, Satterthwait AC, Reed JC (2008) Differential regulation of Bax and Bak by anti-apoptotic Bcl-2 family proteins Bcl-B and Mcl-1. J Biol Chem 283:9580–9586CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  1. 1.Department of BiochemistryHong Kong University of Science and TechnologyClear Water BayHong Kong

Personalised recommendations