Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Oxidative stress in neurodegeneration: cause or consequence?

Abstract

Oxidative stress has long been linked to the neuronal cell death that is associated with certain neurodegenerative conditions. Whether it is a primary cause or merely a downstream consequence of the neurodegenerative process is still an open question, however. The advent of a growing number of in vitro and in vivo models that emulate human disease pathology is aiding scientists in deciphering just where oxidative stress intersects with other cellular events in the emerging roadmap leading to neurodegeneration. Here I review the evidence for oxidative stress in neurodegeneration and how this relates to other cellular events.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1: Schematic illustrating possible oxidative stress pathways in a dopaminergic neuron.
Figure 2

References

  1. Hensley, K. et al. Electrochemical analysis of protein nitrotyrosine and dityrosine in the Alzheimer brain indicates region-specific accumulation. J. Neurosci. 18, 8126–8132 (1998).

    Article  CAS  PubMed  Google Scholar 

  2. Butterfield, D.A., Castegna, A., Lauderback, C.M. & Drake, J. Evidence that amyloid β-peptide-induced lipid peroxidation and its sequelae in Alzheimer's disease brain contribute to neuronal death. Neurobiol. Aging 23, 655–664 (2002).

    Article  PubMed  Google Scholar 

  3. Dexter, D.T. et al. Basal lipid peroxidation in substantia nigra is increased in Parkinson's disease. J. Neurochem. 52, 381–389 (1989).

    Article  CAS  PubMed  Google Scholar 

  4. Pedersen, W.A. et al. Protein modification by the lipid peroxidation product 4-hydroxynonenal in the spinal cords of amyotrophic lateral sclerosis patients. Ann. Neurol. 44, 819–824 (1998).

    Article  CAS  PubMed  Google Scholar 

  5. Beal, M.F. et al. Increased 3-nitrotyrosine in both sporadic and familial amyotrophic lateral sclerosis. Ann. Neurol. 42, 644–654 (1997).

    Article  CAS  PubMed  Google Scholar 

  6. Smith, M.A., Richey Harris, P.L., Sayre, L.M., Beckman, J.S. & Perry, G. Widespread peroxynitrite-mediated damage in Alzheimer's disease. J. Neurosci. 17, 2653–2657 (1997).

    Article  CAS  PubMed  Google Scholar 

  7. Good, P.F., Hsu, A., Werner, P., Perl, D.P. & Olanow, C.W. Protein nitration in Parkinson's disease. J. Neuropathol. Exp. Neurol. 57, 338–342 (1998).

    Article  CAS  PubMed  Google Scholar 

  8. Aoyama, K. et al. Nitration of manganese superoxide dismutase in cerebrospinal fluids is a marker for peroxynitrite-mediated oxidative stress in neurodegenerative diseases. Ann. Neurol. 47, 524–527 (2000).

    Article  CAS  PubMed  Google Scholar 

  9. Giasson, B.I. et al. Oxidative damage linked to neurodegeneration by selective α-synuclein nitration in synucleinopathy lesions. Science 290, 985–989 (2000).

    Article  CAS  PubMed  Google Scholar 

  10. Giasson, B.I. et al. A panel of epitope-specific antibodies detects protein domains distributed throughout human α-synuclein in Lewy bodies of Parkinson's disease. J. Neurosci. Res. 59, 528–533 (2000).

    Article  CAS  PubMed  Google Scholar 

  11. Horiguchi, T. et al. Nitration of tau protein is linked to neurodegeneration in tauopathies. Am. J. Pathol. 163, 1021–1031 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Zemlan, F.P., Thienhaus, O.J. & Bosmann, H.B. Superoxide dismutase activity in Alzheimer's disease: possible mechanism for paired helical filament formation. Brain Res. 476, 160–162 (1989).

    Article  CAS  PubMed  Google Scholar 

  13. Pappolla, M.A., Omar, R.A., Kim, K.S. & Robakis, N.K. Immunohistochemical evidence of oxidative stress in Alzheimer's disease. Am. J. Pathol. 140, 621–628 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Gabbita, S.P., Aksenov, M.Y., Lovell, M.A. & Markesbery, W.R. Decrease in peptide methionine sulfoxide reductase in Alzheimer's disease brain. J. Neurochem. 73, 1660–1666 (1999).

    Article  CAS  PubMed  Google Scholar 

  15. Perry, T.L., Godin, D.V. & Hansen, S. Parkinson's disease: a disorder due to nigral glutathione deficiency? Neurosci. Lett. 33, 305–310 (1982).

    Article  CAS  PubMed  Google Scholar 

  16. Perry, TL. & Yong, V.W. Idiopathic Parkinson's disease, progressive supranuclear palsy and glutathione metabolism in the substantia nigra of patients. Neurosci. Lett. 67, 269–274 (1986).

    Article  CAS  PubMed  Google Scholar 

  17. Pearce, R.K., Owen, A., Daniel, S., Jenner, P. & Marsden, C.D. Alterations in the distribution of glutathione in the substantia nigra in Parkinson's disease. J. Neural Transm. 104, 661–677 (1997).

    Article  CAS  PubMed  Google Scholar 

  18. Riederer, P. et al. Transition metals, ferritin, glutathione, and ascorbic acid in parkinsonian brains. J. Neurochem. 52, 515–520 (1989).

    Article  CAS  PubMed  Google Scholar 

  19. Sofic, E., Paulus, W., Jellinger, K., Riederer, P. & Youdim, M.B. Selective increase of iron in substantia nigra zona compacta of parkinsonian brains. J. Neurochem. 56, 978–982 (1991).

    Article  CAS  PubMed  Google Scholar 

  20. Jellinger, K.A. et al. Iron and ferritin in substantia nigra in Parkinson's disease. Adv. Neurol. 60, 267–272 (1993).

    CAS  PubMed  Google Scholar 

  21. Cudkowicz, M.E. et al. Epidemiology of mutations in superoxide dismutase in amyotrophic lateral sclerosis. Ann. Neurol. 41, 210–221 (1997).

    Article  CAS  PubMed  Google Scholar 

  22. Gurney, M.E. et al. Motor neuron degeneration in mice that express a human Cu,Zn superoxide dismutase mutation. Science 264, 1772–1775 (1994).

    Article  CAS  PubMed  Google Scholar 

  23. Hall, E.D., Andrus, P.K., Oostveen, J.A., Fleck, T.J. & Gurney, M.E. Relationship of oxygen radical-induced lipid peroxidative damage to disease onset and progression in a transgenic model of familial ALS. J. Neurosci. Res. 53, 66–77 (1998).

    Article  CAS  PubMed  Google Scholar 

  24. Warita, H., Hayashi, T., Murakami, T., Manabe, Y. & Abe, K. Oxidative damage to mitochondrial DNA in spinal motoneurons of transgenic ALS mice. Brain Res. Mol. Brain Res. 89, 147–152 (2001).

    Article  CAS  PubMed  Google Scholar 

  25. Dal Canto, M.C. Comparison of pathological alterations in ALS and a murine transgenic model: pathogenetic implications. Clin. Neurosci. 3, 332–337 (1995).

    PubMed  Google Scholar 

  26. Zhang, J., Graham, D.G., Montine, T.J. & Ho, Y.S. Enhanced N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine toxicity in mice deficient in CuZn-superoxide dismutase or glutathione peroxidase. J. Neuropathol. Exp. Neurol. 59, 53–61 (2000).

    Article  CAS  PubMed  Google Scholar 

  27. Klivenyi, P. et al. Mice deficient in cellular glutathione peroxidase show increased vulnerability to malonate, 3-nitropropionic acid, and 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine. J. Neurosci. 20, 1–7 (2000).

    Article  CAS  PubMed  Google Scholar 

  28. Przedborski, S. et al. Transgenic mice with increased Cu/Zn-superoxide dismutase activity are resistant to N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced neurotoxicity. J. Neurosci. 12, 1658–1667 (1992).

    Article  CAS  PubMed  Google Scholar 

  29. Andreassen, O.A. et al. Mice with a partial deficiency of manganese superoxide dismutase show increased vulnerability to the mitochondrial toxins malonate, 3-nitropropionic acid, and MPTP. Exp. Neurol. 167, 189–195 (2001).

    Article  CAS  PubMed  Google Scholar 

  30. Klivenyi, P. et al. Manganese superoxide dismutase overexpression attenuates MPTP toxicity. Neurobiol. Dis. 5, 253–258 (1998).

    Article  CAS  PubMed  Google Scholar 

  31. Klivenyi, P. et al. Inhibition of neuronal nitric oxide synthase protects against MPTP toxicity. Neuroreport 11, 1265–1268 (2000).

    Article  CAS  PubMed  Google Scholar 

  32. Liberatore, G.T. et al. Inducible nitric oxide synthase stimulates dopaminergic neurodegeneration in the MPTP model of Parkinson disease. Nat. Med. 5, 1403–1409 (1999).

    Article  CAS  PubMed  Google Scholar 

  33. Dehmer, T., Lindenau, J., Haid, S., Dichgans, J. & Schulz, J.B. Deficiency of inducible nitric oxide synthase protects against MPTP toxicity in vivo. J. Neurochem. 74, 2213–2216 (2000).

    Article  CAS  PubMed  Google Scholar 

  34. Itzhak, Y., Martin, J.L. & Ali, S.F. Methamphetamine- and 1-methyl-4-phenyl- 1,2,3, 6-tetrahydropyridine-induced dopaminergic neurotoxicity in inducible nitric oxide synthase–deficient mice. Synapse 34, 305–312 (1999).

    Article  CAS  PubMed  Google Scholar 

  35. Zhu, S. et al. Minocycline inhibits cytochrome c release and delays progression of amyotrophic lateral sclerosis in mice. Nature 417, 74–78 (2002).

    Article  CAS  PubMed  Google Scholar 

  36. Wu, D.C. et al. Blockade of microglial activation is neuroprotective in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson disease. J. Neurosci. 22, 1763–1771 (2002).

    Article  CAS  PubMed  Google Scholar 

  37. Du, Y. et al. Minocycline prevents nigrostriatal dopaminergic neurodegeneration in the MPTP model of Parkinson's disease. Proc. Natl. Acad. Sci. USA 98, 14669–14674 (2001).

    Article  CAS  PubMed  Google Scholar 

  38. Yang, L. et al. Minocycline enhances MPTP toxicity to dopaminergic neurons. J. Neurosci. Res. 74, 278–285 (2003).

    Article  CAS  PubMed  Google Scholar 

  39. Sano, M. et al. A controlled trial of selegiline, α-tocopherol, or both as treatment for Alzheimer's disease. The Alzheimer's Disease Cooperative Study. N. Engl. J. Med. 336, 1216–1222 (1997).

    Article  CAS  PubMed  Google Scholar 

  40. Effects of tocopherol and deprenyl on the progression of disability in early Parkinson's disease. The Parkinson Study Group. N. Engl. J. Med. 328, 176–183 (1993).

  41. Desnuelle, C., Dib, M., Garrel, C. & Favier, A. A double-blind, placebo-controlled randomized clinical trial of α-tocopherol (vitamin E) in the treatment of amyotrophic lateral sclerosis. ALS riluzole-tocopherol Study Group. Amyotroph. Lateral Scler. Other Motor Neuron Disord. 2, 9–18 (2001).

    Article  CAS  PubMed  Google Scholar 

  42. Gurney, M.E., Fleck, T.J., Himes, C.S. & Hall, E.D. Riluzole preserves motor function in a transgenic model of familial amyotrophic lateral sclerosis. Neurology 50, 62–66 (1998).

    Article  CAS  PubMed  Google Scholar 

  43. Gurney, M.E. et al. Benefit of vitamin E, riluzole, and gabapentin in a transgenic model of familial amyotrophic lateral sclerosis. Ann. Neurol. 39, 147–157 (1996).

    Article  CAS  PubMed  Google Scholar 

  44. Kieran, D. et al. Treatment with arimoclomol, a coinducer of heat shock proteins, delays disease progression in ALS mice. Nat. Med. 10, 402–405 (2004).

    Article  CAS  PubMed  Google Scholar 

  45. Winklhofer, K.F., Henn, I.H., Kay-Jackson, P.C., Heller, U. & Tatzelt, J. Inactivation of parkin by oxidative stress and C-terminal truncations: a protective role of molecular chaperones. J. Biol. Chem. 278, 47199–47208 (2003).

    Article  CAS  PubMed  Google Scholar 

  46. Bruening, W. et al. Up-regulation of protein chaperones preserves viability of cells expressing toxic Cu/Zn-superoxide dismutase mutants associated with amyotrophic lateral sclerosis. J. Neurochem. 72, 693–699 (1999).

    Article  CAS  PubMed  Google Scholar 

  47. Takeuchi, H. et al. Hsp70 and Hsp40 improve neurite outgrowth and suppress intracytoplasmic aggregate formation in cultured neuronal cells expressing mutant SOD1. Brain Res. 949, 11–22 (2002).

    Article  CAS  PubMed  Google Scholar 

  48. Warrick, J.M. et al. Suppression of polyglutamine-mediated neurodegeneration in Drosophila by the molecular chaperone HSP70. Nat. Genet. 23, 425–428 (1999).

    Article  CAS  PubMed  Google Scholar 

  49. Manning-Bog, A.B., McCormack, A.L., Purisai, M.G., Bolin, L.M. & Di Monte, D.A. α-Synuclein overexpression protects against paraquat-induced neurodegeneration. J. Neurosci. 23, 3095–3099 (2003).

    Article  CAS  PubMed  Google Scholar 

  50. Conway, K.A., Rochet, J.C., Bieganski, R.M. & Lansbury, P.T., Jr. Kinetic stabilization of the α-synuclein protofibril by a dopamine–α-synuclein adduct. Science 294, 1346–1349 (2001).

    Article  CAS  PubMed  Google Scholar 

  51. Volles, M.J. & Lansbury, P.T., Jr. Vesicle permeabilization by protofibrillar α-synuclein is sensitive to Parkinson's disease-linked mutations and occurs by a pore-like mechanism. Biochemistry 41, 4595–4602 (2002).

    Article  CAS  PubMed  Google Scholar 

  52. Lotharius, J. & Brundin, P. Impaired dopamine storage resulting from α-synuclein mutations may contribute to the pathogenesis of Parkinson's disease. Hum. Mol. Genet. 11, 2395–2407 (2002).

    Article  CAS  PubMed  Google Scholar 

  53. Xu, J. et al. Dopamine-dependent neurotoxicity of α-synuclein: a mechanism for selective neurodegeneration in Parkinson disease. Nat. Med. 8, 600–606 (2002).

    Article  CAS  PubMed  Google Scholar 

  54. Abeliovich, A. et al. Mice lacking α-synuclein display functional deficits in the nigrostriatal dopamine system. Neuron 25, 239–252 (2000).

    Article  CAS  PubMed  Google Scholar 

  55. Jha, N., Kumar, M.J., Boonplueang, R. & Andersen, J.K. Glutathione decreases in dopaminergic PC12 cells interfere with the ubiquitin protein degradation pathway: relevance for Parkinson's disease? J. Neurochem. 80, 555–561 (2002).

    Article  CAS  PubMed  Google Scholar 

  56. Friguet, B. & Szweda, L.I. Inhibition of the multicatalytic proteinase (proteasome) by 4-hydroxy-2-nonenal cross-linked protein. FEBS Lett. 405, 21–25 (1997).

    Article  CAS  PubMed  Google Scholar 

  57. Okada, K. et al. 4-Hydroxy-2-nonenal-mediated impairment of intracellular proteolysis during oxidative stress. Identification of proteasomes as target molecules. J. Biol. Chem. 274, 23787–23793 (1999).

    Article  CAS  PubMed  Google Scholar 

  58. Rakhit, R. et al. Monomeric Cu,Zn-superoxide dismutase is a common misfolding intermediate in the oxidation models of sporadic and familial amyotrophic lateral sclerosis. J. Biol. Chem. 279, 15499–15504 (2004).

    Article  CAS  PubMed  Google Scholar 

  59. Behl, C., Davis, J.B., Lesley, R. & Schubert, D. Hydrogen peroxide mediates amyloid-β protein toxicity. Cell 77, 817–827 (1994).

    Article  CAS  PubMed  Google Scholar 

  60. Hsu, L.J. et al. α-Synuclein promotes mitochondrial deficit and oxidative stress. Am. J. Pathol. 157, 401–410 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Ostrerova-Golts, N. et al. The A53T α-synuclein mutation increases iron-dependent aggregation and toxicity. J. Neurosci. 20, 6048–6054 (2000).

    Article  CAS  PubMed  Google Scholar 

  62. Hyun, D.H. et al. Effect of wild-type or mutant Parkin on oxidative damage, nitric oxide, antioxidant defenses, and the proteasome. J. Biol. Chem. 277, 28572–28577 (2002).

    Article  CAS  PubMed  Google Scholar 

  63. Lee, M., Hyun, D., Jenner, P. & Halliwell, B. Effect of overexpression of wild-type and mutant Cu/Zn-superoxide dismutases on oxidative damage and antioxidant defences: relevance to Down's syndrome and familial amyotrophic lateral sclerosis. J. Neurochem. 76, 957–965 (2001).

    Article  CAS  PubMed  Google Scholar 

  64. Lee, M., Hyun, D.H., Halliwell, B. & Jenner, P. Effect of overexpression of wild-type and mutant Cu/Zn-superoxide dismutases on oxidative stress and cell death induced by hydrogen peroxide, 4-hydroxynonenal or serum deprivation: potentiation of injury by ALS-related mutant superoxide dismutases and protection by Bcl-2. J. Neurochem. 78, 209–220 (2001).

    Article  CAS  PubMed  Google Scholar 

  65. Kruman, I.I., Pedersen, W.A., Springer, J.E. & Mattson, M.P. ALS-linked Cu/Zn-SOD mutation increases vulnerability of motor neurons to excitotoxicity by a mechanism involving increased oxidative stress and perturbed calcium homeostasis. Exp. Neurol. 160, 28–39 (1999).

    Article  CAS  PubMed  Google Scholar 

  66. Xie, Z. et al. Peroxynitrite mediates neurotoxicity of amyloid β-peptide1–42- and lipopolysaccharide-activated microglia. J. Neurosci. 22, 3484–3492 (2002).

    Article  CAS  PubMed  Google Scholar 

  67. McNaught, K.S. & Jenner, P. Altered glial function causes neuronal death and increases neuronal susceptibility to 1-methyl-4-phenylpyridinium- and 6-hydroxydopamine-induced toxicity in astrocytic/ventral mesencephalic co-cultures. J. Neurochem. 73, 2469–2476 (1999).

    Article  CAS  PubMed  Google Scholar 

  68. Knott, C., Stern, G. & Wilkin, G.P. Inflammatory regulators in Parkinson's disease: iNOS, lipocortin-1, and cyclooxygenases-1 and -2. Mol. Cell. Neurosci. 16, 724–39 (2000).

    Article  CAS  PubMed  Google Scholar 

  69. Tortarolo, M. et al. Persistent activation of p38 mitogen-activated protein kinase in a mouse model of familial amyotrophic lateral sclerosis correlates with disease progression. Mol. Cell. Neurosci. 23, 180–192 (2003).

    Article  CAS  PubMed  Google Scholar 

  70. Drachman, D.B. et al. Cyclooxygenase 2 inhibition protects motor neurons and prolongs survival in a transgenic mouse model of ALS. Ann. Neurol. 52, 771–778 (2002).

    Article  CAS  PubMed  Google Scholar 

  71. Yoshihara, T. et al. Differential expression of inflammation- and apoptosis-related genes in spinal cords of a mutant SOD1 transgenic mouse model of familial amyotrophic lateral sclerosis. J. Neurochem. 80, 158–167 (2002).

    Article  CAS  PubMed  Google Scholar 

  72. Marques, C.A. et al. Neurotoxic mechanisms caused by the Alzheimer's disease-linked Swedish amyloid precursor protein mutation: oxidative stress, caspases, and the JNK pathway. J. Biol. Chem. 278, 28294–28302 (2003).

    Article  CAS  PubMed  Google Scholar 

  73. Raoul, C. et al. Motoneuron death triggered by a specific pathway downstream of Fas. Potentiation by ALS-linked SOD1 mutations. Neuron 35, 1067–1083 (2002).

    Article  CAS  PubMed  Google Scholar 

  74. Saporito, M.S., Thomas, B.A. & Scott, R.W. MPTP activates c-Jun NH(2)-terminal kinase (JNK) and its upstream regulatory kinase MKK4 in nigrostriatal neurons in vivo. J. Neurochem. 75, 1200–1208 (2000).

    Article  CAS  PubMed  Google Scholar 

  75. Saporito, M.S., Brown, E.M., Miller, M.S. & Carswell, S. CEP-1347/KT-7515, an inhibitor of c-Jun N-terminal kinase activation, attenuates the 1-methyl-4-phenyl tetrahydropyridine-mediated loss of nigrostriatal dopaminergic neurons in vivo. J. Pharmacol. Exp. Ther. 288, 421–427 (1999).

    CAS  PubMed  Google Scholar 

  76. Wang, W. et al. SP600125, a new JNK inhibitor, protects dopaminergic neurons in the MPTP model of Parkinson's disease. Neurosci. Res. 48, 195–202 (2004).

    Article  CAS  PubMed  Google Scholar 

  77. Xia, X.G. et al. Gene transfer of the JNK interacting protein-1 protects dopaminergic neurons in the MPTP model of Parkinson's disease. Proc. Natl. Acad. Sci. USA 98, 10433–10438 (2001).

    Article  CAS  PubMed  Google Scholar 

  78. Trimmer, P.A., Smith, T.S., Jung, A.B. & Bennett, J.P., Jr. Dopamine neurons from transgenic mice with a knockout of the p53 gene resist MPTP neurotoxicity. Neurodegeneration 5, 233–239 (1996).

    Article  CAS  PubMed  Google Scholar 

  79. Emdadul Haque, M. et al. Apoptosis-inducing neurotoxicity of dopamine and its metabolites via reactive quinone generation in neuroblastoma cells. Biochim. Biophys. Acta 1619, 39–52 (2003).

    Article  CAS  PubMed  Google Scholar 

  80. Canals, S., Casarejos, M.J., de Bernardo, S., Rodriguez-Martin, E. & Mena, M.A. Glutathione depletion switches nitric oxide neurotrophic effects to cell death in midbrain cultures: implications for Parkinson's disease. J. Neurochem. 79, 1183–1195 (2001).

    Article  CAS  PubMed  Google Scholar 

  81. Stokes, A.H. et al. Dopamine toxicity in neuroblastoma cells: role of glutathione depletion by L-BSO and apoptosis. Brain Res. 858, 1–8 (2000).

    Article  CAS  PubMed  Google Scholar 

  82. Betarbet, R. et al. Chronic systemic pesticide exposure reproduces features of Parkinson's disease. Nat. Neurosci. 3, 1301–1306 (2000).

    Article  CAS  PubMed  Google Scholar 

  83. German, D.C., Liang, C.L., Manaye, K.F., Lane, K. & Sonsalla, P.K. Pharmacological inactivation of the vesicular monoamine transporter can enhance 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced neurodegeneration of midbrain dopaminergic neurons, but not locus coeruleus noradrenergic neurons. Neuroscience 101, 1063–1069 (2000).

    Article  CAS  PubMed  Google Scholar 

  84. Staal, R.G. & Sonsalla, P.K. Inhibition of brain vesicular monoamine transporter (VMAT2) enhances 1-methyl-4-phenylpyridinium neurotoxicity in vivo in rat striata. J. Pharmacol. Exp. Ther. 293, 336–342 (2000).

    CAS  PubMed  Google Scholar 

  85. Gainetdinov, R.R. et al. Increased MPTP neurotoxicity in vesicular monoamine transporter 2 heterozygote knockout mice. J. Neurochem. 70, 1973–1978 (1998).

    Article  CAS  PubMed  Google Scholar 

  86. Takahashi, N. & Uhl, G. Murine vesicular monoamine transporter 2: molecular cloning and genomic structure. Brain Res. Mol. Brain Res. 49, 7–14 (1997).

    Article  CAS  PubMed  Google Scholar 

  87. Spencer, J.P. et al. Conjugates of catecholamines with cysteine and GSH in Parkinson's disease: possible mechanisms of formation involving reactive oxygen species. J. Neurochem. 71, 2112–2122 (1998).

    Article  CAS  PubMed  Google Scholar 

  88. Berman, S.B. & Hastings, T.G. Dopamine oxidation alters mitochondrial respiration and induces permeability transition in brain mitochondria: implications for Parkinson's disease. J. Neurochem. 73, 1127–1137 (1999).

    Article  CAS  PubMed  Google Scholar 

  89. Dexter, D.T. et al. Indices of oxidative stress and mitochondrial function in individuals with incidental Lewy body disease. Ann. Neurol. 35, 38–44 (1994).

    Article  CAS  PubMed  Google Scholar 

  90. Jha, N. et al. Glutathione depletion in PC12 results in selective inhibition of mitochondrial complex I activity. Implications for Parkinson's disease. J. Biol. Chem. 275, 26096–26101 (2000).

    Article  CAS  PubMed  Google Scholar 

  91. Barker, J.E. et al. Depletion of brain glutathione results in a decrease of glutathione reductase activity; an enzyme susceptible to oxidative damage. Brain Res. 716, 118–122 (1996).

    Article  CAS  PubMed  Google Scholar 

  92. Mattiazzi, M. et al. Mutated human SOD1 causes dysfunction of oxidative phosphorylation in mitochondria of transgenic mice. J. Biol. Chem. 277, 29626–29633 (2002).

    Article  CAS  Google Scholar 

  93. Beretta, S. et al. Mitochondrial dysfunction due to mutant copper/zinc superoxide dismutase associated with amyotrophic lateral sclerosis is reversed by N-acetylcysteine. Neurobiol. Dis. 13, 213–221 (2003).

    Article  CAS  PubMed  Google Scholar 

  94. Khan, S.M. et al. Alzheimer's disease cybrids replicate β-amyloid abnormalities through cell death pathways. Ann. Neurol. 48, 148–155 (2000).

    Article  CAS  PubMed  Google Scholar 

  95. Ward, R.J. et al. Brain iron in the ferrocene-loaded rat: its chelation and influence on dopamine metabolism. Biochem. Pharmacol. 49, 1821–1826 (1995).

    Article  CAS  PubMed  Google Scholar 

  96. Connor, J.R. Iron acquisition and expression of iron regulatory proteins in the developing brain: manipulation by ethanol exposure, iron deprivation and cellular dysfunction. Dev. Neurosci. 16, 233–247 (1994).

    Article  CAS  PubMed  Google Scholar 

  97. Kaur, D. et al. Genetic or pharmacological iron chelation prevents MPTP-induced neurotoxicity in vivo: a novel therapy for Parkinson's disease. Neuron 37, 899–909 (2003).

    Article  CAS  PubMed  Google Scholar 

  98. Cherny, R.A. et al. Treatment with a copper-zinc chelator markedly and rapidly inhibits β-amyloid accumulation in Alzheimer's disease transgenic mice. Neuron 30, 665–676 (2001).

    Article  CAS  PubMed  Google Scholar 

  99. Ritchie, C.W. et al. Metal-protein attenuation with iodochlorhydroxyquin (clioquinol) targeting Aβ amyloid deposition and toxicity in Alzheimer disease: a pilot phase 2 clinical trial. Arch Neurol 60, 1685–1691 (2003).

    Article  PubMed  Google Scholar 

  100. Hottinger, A.F., Fine, E.G., Gurney, M.E., Zurn, A.D. & Aebischer, P. The copper chelator D-penicillamine delays onset of disease and extends survival in a transgenic mouse model of familial amyotrophic lateral sclerosis. Eur. J. Neurosci. 9, 1548–1551 (1997).

    Article  CAS  PubMed  Google Scholar 

  101. Wiedau-Pazos, M. et al. Altered reactivity of superoxide dismutase in familial amyotrophic lateral sclerosis. Science 271, 515–518 (1996).

    Article  CAS  PubMed  Google Scholar 

  102. Yim, M.B. et al. A gain-of-function of an amyotrophic lateral sclerosis–associated Cu,Zn-superoxide dismutase mutant: an enhancement of free radical formation due to a decrease in Km for hydrogen peroxide. Proc. Natl. Acad. Sci. USA 93, 5709–5714 (1996).

    Article  CAS  PubMed  Google Scholar 

  103. Cudkowicz, M.E. et al. Survival in transgenic ALS mice does not vary with CNS glutathione peroxidase activity. Neurology 59, 729–734 (2002).

    Article  CAS  PubMed  Google Scholar 

  104. Liu, R. et al. Increased mitochondrial antioxidative activity or decreased oxygen free radical propagation prevent mutant SOD1-mediated motor neuron cell death and increase amyotrophic lateral sclerosis-like transgenic mouse survival. J. Neurochem. 80, 488–500 (2002).

    Article  CAS  PubMed  Google Scholar 

  105. Lyons, T.J. et al. Mutations in copper-zinc superoxide dismutase that cause amyotrophic lateral sclerosis alter the zinc binding site and the redox behavior of the protein. Proc. Natl. Acad. Sci. USA 93, 12240–12244 (1996).

    Article  CAS  PubMed  Google Scholar 

  106. Estevez, A.G. et al. Induction of nitric oxide–dependent apoptosis in motor neurons by zinc-deficient superoxide dismutase. Science 286, 2498–2500 (1999).

    Article  CAS  PubMed  Google Scholar 

  107. Alexander, M.D. et al. “True” sporadic ALS associated with a novel SOD-1 mutation. Ann. Neurol. 52, 680–683 (2002).

    Article  CAS  PubMed  Google Scholar 

  108. Subramaniam, J.R. et al. Mutant SOD1 causes motor neuron disease independent of copper chaperone-mediated copper loading. Nat. Neurosci. 5, 301–307 (2002).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by the US National Institutes of Health. I apologize to my colleagues whose work was not discussed in detail or cited due to space limitations.

Author information

Authors and Affiliations

Authors

Ethics declarations

Competing interests

The author declares no competing financial interests.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Andersen, J. Oxidative stress in neurodegeneration: cause or consequence?. Nat Med 10 (Suppl 7), S18–S25 (2004). https://doi.org/10.1038/nrn1434

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrn1434

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing