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.

[1]  P. Lansbury,et al.  Vesicle permeabilization by protofibrillar alpha-synuclein is sensitive to Parkinson's disease-linked mutations and occurs by a pore-like mechanism. , 2002, Biochemistry.

[2]  Peter T. Lansbury,et al.  Kinetic Stabilization of the α-Synuclein Protofibril by a Dopamine-α-Synuclein Adduct , 2001, Science.

[3]  G. Wilkin,et al.  Inflammatory Regulators in Parkinson's Disease: iNOS, Lipocortin-1, and Cyclooxygenases-1 and -2 , 2000, Molecular and Cellular Neuroscience.

[4]  C. Rossi,et al.  Persistent activation of p38 mitogen-activated protein kinase in a mouse model of familial amyotrophic lateral sclerosis correlates with disease progression , 2003, Molecular and Cellular Neuroscience.

[5]  S. Lorenzl,et al.  Minocycline enhances MPTP toxicity to dopaminergic neurons , 2003, Journal of neuroscience research.

[6]  M. Miller,et al.  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. , 1999, The Journal of pharmacology and experimental therapeutics.

[7]  D. Bredesen,et al.  Altered Reactivity of Superoxide Dismutase in Familial Amyotrophic Lateral Sclerosis , 1996, Science.

[8]  E. Stadtman,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. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[9]  A. Manning-Boğ,et al.  α-Synuclein Overexpression Protects against Paraquat-Induced Neurodegeneration , 2003, The Journal of Neuroscience.

[10]  A. Chakrabartty,et al.  Monomeric Cu,Zn-superoxide Dismutase Is a Common Misfolding Intermediate in the Oxidation Models of Sporadic and Familial Amyotrophic Lateral Sclerosis*[boxs] , 2004, Journal of Biological Chemistry.

[11]  A. Favier,et al.  A double-blind, placebo-controlled randomized clinical trial of alpha-tocopherol (vitamin E) in the treatment of amyotrophic lateral sclerosis. ALS riluzole-tocopherol Study Group. , 2001, Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases.

[12]  Orla Hardiman,et al.  “True” sporadic ALS associated with a novel SOD‐1 mutation , 2002, Annals of neurology.

[13]  John Hardy,et al.  The A53T α-Synuclein Mutation Increases Iron-Dependent Aggregation and Toxicity , 2000, The Journal of Neuroscience.

[14]  Joseph S. Beckman,et al.  Widespread Peroxynitrite-Mediated Damage in Alzheimer’s Disease , 1997, The Journal of Neuroscience.

[15]  Syed F. Ali,et al.  Methamphetamine‐ and 1‐methyl‐4‐phenyl‐ 1,2,3,6‐tetrahydropyridine‐induced dopaminergic neurotoxicity in inducible nitric oxide synthase‐deficient mice , 1999, Synapse.

[16]  C. Marsden,et al.  Indices of oxidative stress and mitochondrial function in individuals with incidental Lewy body disease , 1994, Annals of neurology.

[17]  C. Marsden,et al.  Alterations in the distribution of glutathione in the substantia nigra in Parkinson's disease , 2005, Journal of Neural Transmission.

[18]  R. Swerdlow,et al.  Alzheimer's disease cybrids replicate β‐amyloid abnormalities through cell death pathways , 2000 .

[19]  H. Horvitz,et al.  Epidemiology of mutations in superoxide dismutase in amyotrophic lateal sclerosis , 1997, Annals of neurology.

[20]  Jeffrey Rothstein,et al.  Mutant SOD1 causes motor neuron disease independent of copper chaperone–mediated copper loading , 2002, Nature Neuroscience.

[21]  P Woodbury,et al.  A controlled trial of selegiline, alpha-tocopherol, or both as treatment for Alzheimer's disease. The Alzheimer's Disease Cooperative Study. , 1997, The New England journal of medicine.

[22]  M. Brin,et al.  Effects of tocopherol and deprenyl on the progression of disability in early Parkinson's disease. , 1993, The New England journal of medicine.

[23]  D. German,et al.  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 , 2000, Neuroscience.

[24]  N. Robakis,et al.  Immunohistochemical evidence of antioxidant stress in Alzheimer's disease , 1992 .

[25]  A. Mackinnon,et al.  Metal-protein attenuation with iodochlorhydroxyquin (clioquinol) targeting Abeta amyloid deposition and toxicity in Alzheimer disease: a pilot phase 2 clinical trial. , 2003, Archives of neurology.

[26]  Dong-Kug Choi,et al.  Blockade of Microglial Activation Is Neuroprotective in the 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine Mouse Model of Parkinson Disease , 2002, The Journal of Neuroscience.

[27]  J. Uney,et al.  Gene transfer of the JNK interacting protein-1 protects dopaminergic neurons in the MPTP model of Parkinson's disease , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[28]  Peter Riederer,et al.  Transition Metals, Ferritin, Glutathione, and Ascorbic Acid in Parkinsonian Brains , 1989, Journal of neurochemistry.

[29]  G. Uhl,et al.  Murine vesicular monoamine transporter 2: molecular cloning and genomic structure. , 1997, Brain research. Molecular brain research.

[30]  Bruce A. Yankner,et al.  Dopamine-dependent neurotoxicity of α-synuclein: A mechanism for selective neurodegeneration in Parkinson disease , 2002, Nature Medicine.

[31]  J. Andersen,et al.  Glutathione decreases in dopaminergic PC12 cells interfere
with the ubiquitin protein degradation pathway: relevance 
for Parkinson's disease? , 2002, Journal of neurochemistry.

[32]  M. Gurney,et al.  Relationship of oxygen radical‐induced lipid peroxidative damage to disease onset and progression in a transgenic model of familial ALS , 1998, Journal of neuroscience research.

[33]  H. Paulson,et al.  Suppression of polyglutamine-mediated neurodegeneration in Drosophila by the molecular chaperone HSP70 , 1999, Nature Genetics.

[34]  Heidi Phillips,et al.  Mice Lacking α-Synuclein Display Functional Deficits in the Nigrostriatal Dopamine System , 2000, Neuron.

[35]  P Riederer,et al.  Selective Increase of Iron in Substantia Nigra Zona Compacta of Parkinsonian Brains , 1991, Journal of neurochemistry.

[36]  J S Beckman,et al.  Induction of nitric oxide-dependent apoptosis in motor neurons by zinc-deficient superoxide dismutase. , 1999, Science.

[37]  P. Sonsalla,et al.  Inhibition of brain vesicular monoamine transporter (VMAT2) enhances 1-methyl-4-phenylpyridinium neurotoxicity in vivo in rat striata. , 2000, The Journal of pharmacology and experimental therapeutics.

[38]  M. Carrì,et al.  Mitochondrial dysfunction due to mutant copper/zinc superoxide dismutase associated with amyotrophic lateral sclerosis is reversed by N-acetylcysteine , 2003, Neurobiology of Disease.

[39]  K. Jellinger,et al.  Iron and ferritin in substantia nigra in Parkinson's disease. , 1993, Advances in neurology.

[40]  S. Paul,et al.  Minocycline prevents nigrostriatal dopaminergic neurodegeneration in the MPTP model of Parkinson's disease , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[41]  C. Epstein,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 , 1992, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[42]  M. Mattson,et al.  ALS-Linked Cu/Zn–SOD Mutation Increases Vulnerability of Motor Neurons to Excitotoxicity by a Mechanism Involving Increased Oxidative Stress and Perturbed Calcium Homeostasis , 1999, Experimental Neurology.

[43]  M. Asanuma,et al.  Apoptosis-inducing neurotoxicity of dopamine and its metabolites via reactive quinone generation in neuroblastoma cells. , 2003, Biochimica et biophysica acta.

[44]  E. Masliah,et al.  α-Synuclein Promotes Mitochondrial Deficit and Oxidative Stress , 2000 .

[45]  Moonhee Lee,et al.  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 , 2001, Journal of neurochemistry.

[46]  R. Scott,et al.  MPTP Activates c‐Jun NH2‐Terminal Kinase (JNK) and Its Upstream Regulatory Kinase MKK4 in Nigrostriatal Neurons In Vivo , 2000, Journal of neurochemistry.

[47]  F. Zemlan,et al.  Superoxide dismutase activity in Alzheimer's disease: possible mechanism for paired helical filament formation , 1989, Brain Research.

[48]  J. Connor,et al.  Iron acquisition and expression of iron regulatory proteins in the developing brain: manipulation by ethanol exposure, iron deprivation and cellular dysfunction. , 1994, Developmental neuroscience.

[49]  H. Aanstoot Laboratory Standards in the Assessment of the Quality of Care , 1998, Hormone Research in Paediatrics.

[50]  C. Masters,et al.  Treatment with a Copper-Zinc Chelator Markedly and Rapidly Inhibits β-Amyloid Accumulation in Alzheimer's Disease Transgenic Mice , 2001, Neuron.

[51]  M. Gurney,et al.  Motor neuron degeneration in mice that express a human Cu,Zn superoxide dismutase mutation. , 1994, Science.

[52]  M. Mattson,et al.  Protein modification by the lipid peroxidation product 4‐hydroxynonenal in the spinal cords of amyotrophic lateral sclerosis patients , 1998, Annals of neurology.

[53]  J. Dichgans,et al.  Deficiency of Inducible Nitric Oxide Synthase Protects Against MPTP Toxicity In Vivo , 2000, Journal of neurochemistry.

[54]  J. Rothstein,et al.  Cyclooxygenase 2 inhibition protects motor neurons and prolongs survival in a transgenic mouse model of ALS , 2002, Annals of neurology.

[55]  W. Markesbery,et al.  Decrease in Peptide Methionine Sulfoxide Reductase in Alzheimer's Disease Brain , 1999, Journal of neurochemistry.

[56]  M. Gurney,et al.  Riluzole preserves motor function in a transgenic model of familial amyotrophic lateral sclerosis , 1998, Neurology.

[57]  Todd B. Sherer,et al.  Chronic systemic pesticide exposure reproduces features of Parkinson's disease , 2000, Nature Neuroscience.

[58]  Shotai Kobayashi,et al.  Nitration of manganese superoxide dismutase in cerebrospinal fluids is a marker for peroxynitrite‐mediated oxidative stress in neurodegenerative diseases , 2000, Annals of neurology.

[59]  N. Hattori,et al.  Effect of Wild-type or Mutant Parkin on Oxidative Damage, Nitric Oxide, Antioxidant Defenses, and the Proteasome* , 2002, The Journal of Biological Chemistry.

[60]  Wendy Bruening,et al.  Up‐Regulation of Protein Chaperones Preserves Viability of Cells Expressing Toxic Cu/Zn‐Superoxide Dismutase Mutants Associated with Amyotrophic Lateral Sclerosis , 1999, Journal of neurochemistry.

[61]  C. Haass,et al.  Neurotoxic Mechanisms Caused by the Alzheimer's Disease-linked Swedish Amyloid Precursor Protein Mutation , 2003, Journal of Biological Chemistry.

[62]  J. Trojanowski,et al.  A panel of epitope‐specific antibodies detects protein domains distributed throughout human α‐synuclein in lewy bodies of Parkinson's disease , 2000, Journal of neuroscience research.

[63]  Robert H. Brown,et al.  Increased 3‐nitrotyrosine in both sporadic and familial amyotrophic lateral sclerosis , 1997, Annals of neurology.

[64]  Hiroshi Nishimune,et al.  Motoneuron Death Triggered by a Specific Pathway Downstream of Fas Potentiation by ALS-Linked SOD1 Mutations , 2002, Neuron.

[65]  Geoffrey Burnstock,et al.  Treatment with arimoclomol, a coinducer of heat shock proteins, delays disease progression in ALS mice , 2004, Nature Medicine.

[66]  Moonhee Lee,et al.  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 , 2001, Journal of neurochemistry.

[67]  O. Andreassen,et al.  Inhibition of neuronal nitric oxide synthase protects against MPTP toxicity , 2000, Neuroreport.

[68]  M. Gurney,et al.  The Copper Chelator d‐Penicillamine Delays Onset of Disease and Extends Survival in a Transgenic Mouse Model of Familial Amyotrophic Lateral Sclerosis , 1997, The European journal of neuroscience.

[69]  Ming-tao Li,et al.  SP600125, a new JNK inhibitor, protects dopaminergic neurons in the MPTP model of Parkinson’s disease , 2004, Neuroscience Research.

[70]  D. Perl,et al.  Protein Nitration in Parkinson's Disease , 1998, Journal of neuropathology and experimental neurology.

[71]  Takeshi Hayashi,et al.  Oxidative damage to mitochondrial DNA in spinal motoneurons of transgenic ALS mice. , 2001, Brain research. Molecular brain research.

[72]  Subramanian Rajagopalan,et al.  Genetic or Pharmacological Iron Chelation Prevents MPTP-Induced Neurotoxicity In Vivo A Novel Therapy for Parkinson's Disease , 2003, Neuron.

[73]  J. Bolaños,et al.  Depletion of brain glutathione results in a decrease of glutathione reductase activity; an enzyme susceptible to oxidative damage , 1996, Brain Research.

[74]  W. Markesbery,et al.  Electrochemical Analysis of Protein Nitrotyrosine and Dityrosine in the Alzheimer Brain Indicates Region-Specific Accumulation , 1998, The Journal of Neuroscience.

[75]  Betty Y. S. Kim,et al.  Minocycline inhibits cytochrome c release and delays progression of amyotrophic lateral sclerosis in mice , 2002, Nature.

[76]  M. Cudkowicz,et al.  Survival in transgenic ALS mice does not vary with CNS glutathione peroxidase activity , 2002, Neurology.

[77]  S. Canals,et al.  Glutathione depletion switches nitric oxide neurotrophic effects to cell death in midbrain cultures: implications for Parkinson's disease , 2001, Journal of neurochemistry.

[78]  A. Favier,et al.  A double-blind, placebo-controlled randomized clinical trial of α-tocopherol (vitamin E) in the treatment of amyotrophic lateral sclerosis , 2001 .

[79]  G. Sobue,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 , 2002, Journal of neurochemistry.

[80]  T. Morgan,et al.  Peroxynitrite Mediates Neurotoxicity of Amyloid β-Peptide1–42- and Lipopolysaccharide-Activated Microglia , 2002, The Journal of Neuroscience.

[81]  O. Andreassen,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 , 2000, The Journal of Neuroscience.

[82]  K. Vrana,et al.  Dopamine toxicity in neuroblastoma cells: role of glutathione depletion by l-BSO and apoptosis , 2000, Brain Research.

[83]  C. Behl,et al.  Hydrogen peroxide mediates amyloid β protein toxicity , 1994, Cell.

[84]  A. Levey,et al.  Increased MPTP Neurotoxicity in Vesicular Monoamine Transporter 2 Heterozygote Knockout Mice , 1998, Journal of neurochemistry.

[85]  J. Trojanowski,et al.  Oxidative damage linked to neurodegeneration by selective alpha-synuclein nitration in synucleinopathy lesions. , 2000, Science.

[86]  M. Beal,et al.  Manganese Superoxide Dismutase Overexpression Attenuates MPTP Toxicity , 1998, Neurobiology of Disease.

[87]  D. Gozal,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 , 2002, Journal of neurochemistry.

[88]  Ted M. Dawson,et al.  Inducible nitric oxide synthase stimulates dopaminergic neurodegeneration in the MPTP model of Parkinson disease , 1999, Nature Medicine.

[89]  T. Montine,et al.  Enhanced N‐Methyl‐4‐Phenyl‐1,2,3,6‐Tetrahydropyridine Toxicity in Mice Deficient in CuZn‐Superoxide Dismutase or Glutathione Peroxidase , 2000, Journal of neuropathology and experimental neurology.

[90]  B. Friguet,et al.  Inhibition of the multicatalytic proteinase (proteasome) by 4‐hydroxy‐2‐nonenal cross‐linked protein , 1997, FEBS letters.

[91]  G. Sobue,et al.  Hsp70 and Hsp40 improve neurite outgrowth and suppress intracytoplasmic aggregate formation in cultured neuronal cells expressing mutant SOD1 , 2002, Brain Research.

[92]  Voon Wee Yong,et al.  Idiopathic Parkinson's disease, progressive supranuclear palsy and glutathione metabolism in the substantia nigra of patients , 1986, Neuroscience Letters.

[93]  L. Ellerby,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. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[94]  J. Bennett,et al.  Dopamine neurons from transgenic mice with a knockout of the p53 gene resist MPTP neurotoxicity. , 1996, Neurodegeneration : a journal for neurodegenerative disorders, neuroprotection, and neuroregeneration.

[95]  M. Gurney,et al.  Benefit of vitamin E, riluzole, and gababapentin in a transgenic model of familial amyotrophic lateral sclerosis , 1996, Annals of neurology.

[96]  C. Marsden,et al.  Basal Lipid Peroxidation in Substantia Nigra Is Increased in Parkinson's Disease , 1989, Journal of neurochemistry.

[97]  A. Lees,et al.  Conjugates of Catecholamines with Cysteine and GSH in Parkinson's Disease: Possible Mechanisms of Formation Involving Reactive Oxygen Species , 1998, Journal of neurochemistry.

[98]  D. Godin,et al.  Parkinson's disease: A disorder due to nigral glutathione deficiency? , 1982, Neuroscience Letters.

[99]  D. Dexter,et al.  Brain iron in the ferrocene-loaded rat: its chelation and influence on dopamine metabolism. , 1995, Biochemical pharmacology.

[100]  J. Trojanowski,et al.  Nitration of tau protein is linked to neurodegeneration in tauopathies. , 2003, The American journal of pathology.

[101]  K. Winklhofer,et al.  Inactivation of Parkin by Oxidative Stress and C-terminal Truncations , 2003, Journal of Biological Chemistry.

[102]  M. D. Dal Canto Comparison of pathological alterations in ALS and a murine transgenic model: pathogenetic implications. , 1995, Clinical neuroscience.

[103]  M. Beal,et al.  Mutated Human SOD1 Causes Dysfunction of Oxidative Phosphorylation in Mitochondria of Transgenic Mice* , 2002, The Journal of Biological Chemistry.

[104]  Patrik Brundin,et al.  Impaired dopamine storage resulting from alpha-synuclein mutations may contribute to the pathogenesis of Parkinson's disease. , 2002, Human molecular genetics.

[105]  D. Mc Comparison of pathological alterations in ALS and a murine transgenic model: pathogenetic implications. , 1995 .

[106]  D. Butterfield,et al.  Evidence that amyloid beta-peptide-induced lipid peroxidation and its sequelae in Alzheimer’s disease brain contribute to neuronal death , 2002, Neurobiology of Aging.

[107]  H. Forman,et al.  Glutathione Depletion in PC12 Results in Selective Inhibition of Mitochondrial Complex I Activity , 2000, The Journal of Biological Chemistry.

[108]  S. Berman,et al.  Dopamine Oxidation Alters Mitochondrial Respiration and Induces Permeability Transition in Brain Mitochondria , 1999, Journal of neurochemistry.

[109]  K. McNaught,et al.  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 , 1999, Journal of neurochemistry.

[110]  Ole A. Andreassen,et al.  Mice with a Partial Deficiency of Manganese Superoxide Dismutase Show Increased Vulnerability to the Mitochondrial Toxins Malonate, 3-Nitropropionic Acid, and MPTP , 2001, Experimental Neurology.