Nature Reviews Neuroscience 5, S18–S25 (2004)

Oxidative stress in neurodegeneration: cause or consequence?

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.

Julie K Andersen

Buck Institute, 8001 Redwood Blvd., Novato, California 94945, USA. jandersen@buckinstitute.org

Published online: 1 July 2004
doi:10.1038/nrn1434

Because of its high metabolic rate and relatively reduced capacity for cellular regeneration compared with other organs, the brain is believed to be particularly susceptible to the damaging affects of ROS. In cases of PD, AD and ALS, various indices of ROS damage have been reported within the specific brain region that undergoes selective neurodegeneration. For example, markers for lipid peroxidation, including 4-HYDROXYNONENAL (4-HNE) and malondialdehyde (MDA), have been identified in the cortex and hippocampus of patients with AD, the SUBSTANTIA NIGRA of patients with PD and in spinal fluid from patients with ALS^{1, 2, 3, 4, 5}. Protein nitration, a marker of protein oxidation, has been demonstrated to be elevated in the hippocampus and neocortex of individuals with AD, in LEWY BODIES in cases of PD and within motor neurons in ALS^{6, 7, 8}. Surprisingly, several of these oxidative events seem to be fairly target specific. For instance, nitration of tyrosine residues within the -synuclein protein is found to accumulate in the Lewy bodies that are associated with PD and other synucleopathies^{9, 10} and within the tau protein in AD¹¹. Oxidative stress is therefore consistently associated with these diseases.

In recent years, several genetically engineered mouse lines that emulate the oxidative changes observed in various neurodegenerative diseases have been created, and these mice have been examined for their ability to model disease pathology. Transgenic mouse lines expressing various human familial ALS–SOD1 mutations show not only motor neuron degeneration but also elevated lipid peroxidation, DNA oxidation and protein nitration within the affected cells^{22, 23, 24, 25}. Notably, research conducted on these transgenic lines has revealed that these mutations seem to result in a toxic gain of function unrelated to the ability of SOD1 to reduce O₂^- to H₂O₂. Some researchers hypothesize that the toxic effects of the mutations might still indirectly involve an increase in oxidative damage owing to the ability of mutant ALS–SOD1 to act as a peroxidase, superoxide reductase, or to increase ONOO^- levels as a consequence of heightened O₂^- production and its subsequent reaction with NO (Box 3). GSHPx- and SOD1-deficient mice, and mice that are null for the mitochondrial manganese-containing SOD2 gene, are more sensitive to the toxic effects of the PD-inducing agent 1-methyl-4-phenyl-1,2,3,6, tetrapyridine (MPTP), whereas transgenics with mutations in SOD1 and SOD2 are more resistant^{26, 27, 28, 29, 30}. Expression of iNOS, the inducible form of nitric oxide synthase (NOS), which is found primarily within brain glia, is found to contribute to neurodegeneration associated with expression of human ALS–SOD1 mutations and MPTP administration, whereas both iNOS-null mice and mice that are deficient for the neuronal form of NOS (nNOS) are more susceptible to MPTP toxicity^{31, 32, 33, 34}. Such results have led to the testing of pharmacological agents that block the oxidative cellular events that seem to be involved in the ensuing neurodegeneration. Minocycline, which is believed to act in part by blocking the activity of iNOS, has been shown to prevent neurodegeneration both in ALS–SOD transgenic mice and in wild-type mice after MPTP administration, although this claim has been disputed in the latter case^{35, 36, 37, 38}. Metal chelators have been demonstrated to prevent plaque formation in AD mouse models that express the amyloid precursor protein (APP), and to prevent dopaminergic cell loss in MPTP-treated mice (Box 2). These are only a few examples of the plethora of findings in recent years based on the modeling of human neurodegenerative diseases in animal models. These findings have helped to increase scientists' understanding of the role of oxidative stress in accompanying neuronal cell loss.

Increased oxidative alterations to proteins such as -synuclein in PD, -AMYLOID in AD and SOD1 in ALS might result in increased protein misfolding and impaired degradation. This, in turn, might cause the toxic accumulation of soluble protofibrils or insoluble aggregates within the diseased brain that can contribute to neurodegeneration. How does this occur? Oxidative stress increases with age in the brain, and neurons might be particularly affected because they are postmitotic. The ability of cells to respond to oxidative protein damage also seems to decline with age and might contribute to protein buildup. A decline in induction of heat shock proteins (HSPs), for instance, can result in an increase in oxidatively damaged proteins that might be resistant to ubiquitinylation and degradation by the 26S proteasome. Depletion of soluble HSPs has been proposed to be an important influence in the cellular neurodegeneration that is associated with ALS. Indeed, pharmacological induction of HSPs by the agent arimoclomol has recently been demonstrated to slow disease progression in ALS–SOD1 transgenic mouse models⁴⁴. Increased expression of HSP70 has been suggested to protect against the toxic effects associated with human PD mutations in both the -synuclein and parkin genes, including oxidative damage that results in protein misfolding^{45, 46, 47, 48, 49}.

Each of these diseases might have special features that contribute to the interaction between oxidative stress and specific protein misfolding. In PD, for example, dopamine metabolism yields oxidative by-products such as O₂^-, H₂O₂ and dopaminergic quinines, which might be involved, along with iron, in the oxidation of -synuclein (Fig. 1). -Synuclein has been suggested to bind to and permeabilize synaptic vesicles, thereby increasing the amount of dopamine present in the relatively acidic environment of the cytoplasm, where it is more likely to be oxidized^{50, 51, 52}. Therefore, -synuclein might itself initiate events that lead to its own oxidative damage. Dopaminergic cell death in embryonic midbrain cultures transfected with a mutant form of the human A53T -synuclein gene is attenuated by depleting cells of intracellular dopamine by inhibiting its synthesis or by antioxidant treatment. This indicates that loss of cell viability through -synuclein expression results in loss of cell viability resulting from dopamine-driven oxidative events⁵³. Synuclein-null mice are more resistant to MPTP toxicity, perhaps because of attenuation of synaptic dopamine release⁵⁴. Oxidized -synuclein might, in turn, not be properly recognized by the ubiquitin-proteasome protein degradation system, resulting in its buildup in the cell. GSH depletion in cultured dopaminergic cells mimicking PD can result in inhibitory oxidation of E1 and E2 ubiquitin pathway enzymes, resulting in decreased ubiquitinylation of oxidized proteins, which might contribute to the upsurge of their amounts in the cytoplasm and inhibition of proteasomal function⁵⁵. Increased concentrations of 4-HNE, which might be produced by GSH depletion in PD and are present in affected tissues in PD, AD and ALS, can further enhance cross-linking of damaged proteins. Conjugates of 4-HNE and protein have been reported to inhibit proteasomal function⁵⁶, and the proteasome itself might be a direct target⁵⁷. Oxidation of both ALS–SOD1 mutant and wild-type SOD1 proteins in vitro results in increased aggregation of the protein itself⁵⁸.

Fig. 1
		Figure 1 | Schematic illustrating possible oxidative stress pathways in a dopaminergic neuron.

It is also possible that the proteins that are involved in protofibril formation might themselves produce oxidative stress. -Amyloid has been demonstrated to produce H₂O₂ in cultured cells⁵⁹. Transfection of cells with mutant human A53T -synuclein or parkin genes results in increased oxidation of both proteins and lipids^{60, 61, 62}. Expression of human ALS–SOD1 mutant genes in culture resulted in an increase in indices of oxidation, as well as increased susceptibility to oxidative stress^{63, 64}. In primary motor neuron cultures isolated from these animals, oxidative stress is elevated in correlation with increased cellular demise, which is preventable by treatment with various antioxidant agents⁶⁵. Although the existing data make it extremely difficult to determine whether oxidative stress or protein aggregation is the initiating event, these two processes clearly have an important impact on one another.

Glial cell activation in response to cellular damage, including oxidative injury, involves a complex range of responses, including increased expression of genes that are involved in both NO and cytokine synthesis. When released by glia as a nonspecific means of destroying damaged cells, these agents can result in subsequent neurodegeneration. H₂O₂ released by activated glia, though itself fairly innocuous, can be altered by peroxidases to form hypochlorous acid (HOCl), which is highly toxic to cells. ONOO^- formed through the interaction of NO with O₂^- can result in both nitration of tyrosines and nitrosylation of cysteines within both enzymes and structural proteins.

Activation of microglial and ensuing ONOO^- production has recently been linked to -amyloid toxicity in cultured neurons⁶⁶. Culture of activated astrocytes with primary dopaminergic cultures leads to increased susceptibility of dopaminergic neurons to MPP⁺-mediated cell death, perhaps owing to glial-mediated oxidative stress⁶⁷. Glial iNOS concentrations are increased in the midbrain of individuals with PD⁶⁸. Persistent activation of the p38 mitogen-activated protein kinase (MAPK) within affected motor neurons and reactive glia in an ALS–SOD1 mouse model has been demonstrated to correlate with disease progression⁶⁹. This MAPK protein can be activated by oxidative stress and inflammation, and can in turn act to enhance glial NO production. Inhibition of cyclooxygenase-2, which also plays a role in ROS production associated with glial activation, results in a delay in disease onset in ALS–SOD transgenics⁷⁰. Using cDNA microarray analysis, mRNA levels of several genes that are involved in the inflammatory response were recently found to be upregulated in ALS–SOD1 mice at a presymptomatic stage of motor neurodegeneration⁷¹. Production of oxidative stress associated with an active immune response therefore seems to be another prominent feature in pathology associated with all three of these diseases.

Not only might oxidative stress result in accidental damage to cells, but it might also actively trigger intracellular signaling pathways that lead to cellular demise. Although there is evidence of programmed cell death (PCD) in AD and various models of the disease, the role of oxidative stress in this process is yet to be delineated, although it might be tied to observed -amyloid oligomerization and mitochondrial dysfunction. Expression of the familial Swedish double -amyloid precursor protein mutation in cultured cells results in increased susceptibility to exogenous oxidative stress, which appears to trigger apoptotic cell death by various pathways⁷². Caspase activation within motor neurons from ALS–SOD1 transgenics has been reported to be NOS dependent and to be triggered by NO itself⁷³. Caspase activation after MPTP intoxication seems to occur by means of the JNK signaling pathway⁷⁴. MPTP-mediated cell death is markedly attenuated through the use of JNK inhibitors or adenoviral transfer of the inhibitory JNK-binding protein JIP-1 into the substantia nigra^{75, 76, 77}. Its activation could be the consequence of oxidative damage to DNA. MPTP-induced DNA damage also seems to activate the p53 tumor suppressor gene, resulting in PCD through induction of the pro-apoptotic factor Bax-1. MPTP toxicity is attenuated in midbrain cultures from p53-null mice and by in vivo administration of p53 inhibitors⁷⁸. Notably, GSH reduction itself has been shown to induce PCD in dopaminergic neurons, and its addition has been shown to prevent dopamine-dependent neurotoxicity^{79, 80, 81}.

Epidemiological studies have identified certain environmental agents, including pesticides and herbicides, as being risk factors for PD. Animals that are treated with the herbicide rotenone display selective neuropathology that is extremely reminiscent of the disease state⁸². Both MPTP and rotenone are selective complex I inhibitors. Complex I inhibition by MPTP can directly result in increased oxidative stress, particularly through the production of O₂^-. It also results in reduced mitochondrial function, including decreased ATP generation. ATP is necessary for several cellular processes, including the loading of dopamine into synaptic vesicles by the vesicular monoamine transporter (VMAT2). Its depletion can result in increased cytoplasmic dopamine levels, which might in turn result in indirect production of oxidative stress through the generation of dopamine oxidation by-products. VMAT2-heterozygous null mice or rodents treated with VMAT2 inhibitors are more sensitive to the effects of MPTP or MPP⁺ (refs. 83, 84, 85, 86). Because systemic administration of rotenone does not lead to inhibition sufficient to impair mitochondrial function, it has been proposed that its toxic effects probably involve increased oxidative stress mediated through complex I inhibition⁸². Rotenone administration also seems to result in increased -synuclein aggregation and formation of Lewy bodies in vivo, which might be a consequence of increased oxidative stress.

Reduced mitochondrial function in correlation with increased mitochondrial protein and lipid oxidation was noted in isolated mitochondria from ALS–SOD1 transgenics⁹². Expression of ALS–SOD1 mutants in cultured cells results in mitochondrial dysfunction, which can be reversed by treatment with the thiol-reducing agent N-acetylcysteine⁹³. Cybrids created by fusing mitochondrial DNA from sporadic AD patients with normal cytoplasm display decreased mitochondrial function and increased -amyloid deposition, which can be reversed by antioxidant treatment⁹⁴.

It is still unclear whether oxidative stress is the primary initiating event that is associated with neurodegeneration in PD, AD and ALS. However, a growing body of evidence implicates it as being involved in at least the propagation of cellular injury that leads to neuropathology in these various conditions. It is intimately linked with an integrated series of cellular phenomena, which all seem to contribute to neuronal demise. Interaction between these various components is not necessarily a cascade but might be a cycle of events, of which oxidative stress is a major component (Fig. 2). Inhibition of oxidative stress therapeutically might act to 'break the cycle' of cell death. Therefore, many researchers in the neurodegenerative field are concentrating on modulating or emulating the protective effects of key enzymatic components that regulate oxidative stress, with the aim of developing rational drug or genetic therapy. The creation of numerous cell and animal models has aided enormously in this effort. More sophisticated models, which selectively target the effects of oxidative stress to the specifically affected brain region in each of these diseases, are currently being developed, and should greatly advance our understanding of the involvement of oxidative stress in selective neurodegenerative events. Many current animal models, though accurately emulating portions of the specific pathology, might not completely reproduce it, and not all models recapitulate the chronic nature of these disorders. Combinations of these various models are already being attempted, and this approach might further improve their usefulness in the investigation of neurodegenerative disease, including the role of oxidative stress in this process.

Fig. 2
		Figure 2 | ROS production as a major player in the cycle of events leading to neurodegeneration.

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.

Competing interests statement:

The author declares that she has no competing financial interests.

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).
2. Butterfield, D.A., Castegna, A., Lauderback, C.M. & Drake, J. Evidence that amyloid -peptide-induced lipid peroxidation and its sequelae in Alzheimer's disease brain contribute to neuronal death. Neurobiol. Aging 23, 655−664 (2002). | Article |
3. Dexter, D.T. et al. Basal lipid peroxidation in substantia nigra is increased in Parkinson's disease. J. Neurochem. 52, 381−389 (1989).
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).
5. Beal, M.F. et al. Increased 3-nitrotyrosine in both sporadic and familial amyotrophic lateral sclerosis. Ann. Neurol. 42, 644−654 (1997).
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).
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).
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 |
9. Giasson, B.I. et al. Oxidative damage linked to neurodegeneration by selective -synuclein nitration in synucleinopathy lesions. Science 290, 985−989 (2000). | Article |
10. Giasson, B.I. et al. A panel of epitope-specific antibodies detects protein domains distributed throughout human -synuclein in Lewy bodies of Parkinson's disease. J. Neurosci. Res. 59, 528−533 (2000). | Article |
11. Horiguchi, T. et al. Nitration of tau protein is linked to neurodegeneration in tauopathies. Am. J. Pathol. 163, 1021−1031 (2003).
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 |
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).
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 |
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).
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 |
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).
18. Riederer, P. et al. Transition metals, ferritin, glutathione, and ascorbic acid in parkinsonian brains. J. Neurochem. 52, 515−520 (1989).
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).
20. Jellinger, K.A. et al. Iron and ferritin in substantia nigra in Parkinson's disease. Adv. Neurol. 60, 267−272 (1993).
21. Cudkowicz, M.E. et al. Epidemiology of mutations in superoxide dismutase in amyotrophic lateral sclerosis. Ann. Neurol. 41, 210−221 (1997).
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).
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 |
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).
25. Dal Canto, M.C. Comparison of pathological alterations in ALS and a murine transgenic model: pathogenetic implications. Clin. Neurosci. 3, 332−337 (1995).
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).
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).
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).
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 |
30. Klivenyi, P. et al. Manganese superoxide dismutase overexpression attenuates MPTP toxicity. Neurobiol. Dis. 5, 253−258 (1998). | Article |
31. Klivenyi, P. et al. Inhibition of neuronal nitric oxide synthase protects against MPTP toxicity. Neuroreport 11, 1265−1268 (2000).
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 |
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 |
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 |
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 |
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).
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 |
38. Yang, L. et al. Minocycline enhances MPTP toxicity to dopaminergic neurons. J. Neurosci. Res. 74, 278−285 (2003). | Article |
39. Sano, M. et al. A controlled trial of selegiline, -tocopherol, or both as treatment for Alzheimer's disease. The Alzheimer's Disease Cooperative Study. N. Engl. J. Med. 336, 1216−1222 (1997). | Article |
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). | Article |
41. Desnuelle, C., Dib, M., Garrel, C. & Favier, A. A double-blind, placebo-controlled randomized clinical trial of -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 |
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 |
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).
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 |
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 |
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 |
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 |
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 |
49. Manning-Bog, A.B., McCormack, A.L., Purisai, M.G., Bolin, L.M. & Di Monte, D.A. -Synuclein overexpression protects against paraquat-induced neurodegeneration. J. Neurosci. 23, 3095−3099 (2003).
50. Conway, K.A., Rochet, J.C., Bieganski, R.M. & Lansbury, P.T., Jr. Kinetic stabilization of the -synuclein protofibril by a dopamine−-synuclein adduct. Science 294, 1346−1349 (2001). | Article |
51. Volles, M.J. & Lansbury, P.T., Jr. Vesicle permeabilization by protofibrillar -synuclein is sensitive to Parkinson's disease-linked mutations and occurs by a pore-like mechanism. Biochemistry 41, 4595−4602 (2002). | Article |
52. Lotharius, J. & Brundin, P. Impaired dopamine storage resulting from -synuclein mutations may contribute to the pathogenesis of Parkinson's disease. Hum. Mol. Genet. 11, 2395−2407 (2002). | Article |
53. Xu, J. et al. Dopamine-dependent neurotoxicity of -synuclein: a mechanism for selective neurodegeneration in Parkinson disease. Nat. Med. 8, 600−606 (2002). | Article |
54. Abeliovich, A. et al. Mice lacking -synuclein display functional deficits in the nigrostriatal dopamine system. Neuron 25, 239−252 (2000). | Article |
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 |
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 |
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 |
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 |
59. Behl, C., Davis, J.B., Lesley, R. & Schubert, D. Hydrogen peroxide mediates amyloid- protein toxicity. Cell 77, 817−827 (1994). | Article |
60. Hsu, L.J. et al. -Synuclein promotes mitochondrial deficit and oxidative stress. Am. J. Pathol. 157, 401−410 (2000).
61. Ostrerova-Golts, N. et al. The A53T -synuclein mutation increases iron-dependent aggregation and toxicity. J. Neurosci. 20, 6048−6054 (2000).
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 |
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 |
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 |
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 |
66. Xie, Z. et al. Peroxynitrite mediates neurotoxicity of amyloid -peptide1−42- and lipopolysaccharide-activated microglia. J. Neurosci. 22, 3484−3492 (2002).
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 |
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 |
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 |
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 |
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 |
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 |
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 |
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 |
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).
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 |
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 |
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 |
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).
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 |
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 |
82. Betarbet, R. et al. Chronic systemic pesticide exposure reproduces features of Parkinson's disease. Nat. Neurosci. 3, 1301−1306 (2000).
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 |
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).
85. Gainetdinov, R.R. et al. Increased MPTP neurotoxicity in vesicular monoamine transporter 2 heterozygote knockout mice. J. Neurochem. 70, 1973−1978 (1998).
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 |
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).
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 |
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).
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 |
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 |
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 |
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 |
94. Khan, S.M. et al. Alzheimer's disease cybrids replicate -amyloid abnormalities through cell death pathways. Ann. Neurol. 48, 148−155 (2000). | Article |
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 |
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).
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 |
98. Cherny, R.A. et al. Treatment with a copper-zinc chelator markedly and rapidly inhibits -amyloid accumulation in Alzheimer's disease transgenic mice. Neuron 30, 665−676 (2001). | Article |
99. Ritchie, C.W. et al. Metal-protein attenuation with iodochlorhydroxyquin (clioquinol) targeting A amyloid deposition and toxicity in Alzheimer disease: a pilot phase 2 clinical trial. Arch Neurol 60, 1685−1691 (2003). | Article |
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).
101. Wiedau-Pazos, M. et al. Altered reactivity of superoxide dismutase in familial amyotrophic lateral sclerosis. Science 271, 515−518 (1996).
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 K_m for hydrogen peroxide. Proc. Natl. Acad. Sci. USA 93, 5709−5714 (1996). | Article |
103. Cudkowicz, M.E. et al. Survival in transgenic ALS mice does not vary with CNS glutathione peroxidase activity. Neurology 59, 729−734 (2002).
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 |
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 |
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 |
107. Alexander, M.D. et al. "True" sporadic ALS associated with a novel SOD-1 mutation. Ann. Neurol. 52, 680−683 (2002). | Article |
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 |