Evidence of Increased Oxidative Damage in Both Sporadic and Familial Amyotrophic Lateral Sclerosis

Abstract: Some cases of autosomal dominant familial amyotrophic lateral sclerosis (FALS) are associated with mutations in the gene encoding Cu/Zn superoxide dismutase (SOD1), suggesting that oxidative damage may play a role in ALS pathogenesis. To further investigate the biochemical features of FALS and sporadic ALS (SALS), we examined markers of oxidative damage to protein, lipids, and DNA in motor cortex (Brodmann area 4), parietal cortex (Brodmann area 40), and cerebellum from control subjects, FALS patients with and without known SOD mutations, SALS patients, and disease controls (Pick's disease, progressive supranuclear palsy, diffuse Lewy body disease). Protein carbonyl and nuclear DNA 8‐hydroxy‐2′‐deoxyguanosine (OH8dG) levels were increased in SALS motor cortex but not in FALS patients. Malondialdehyde levels showed no significant changes. Immunohistochemical studies showed increased neuronal staining for hemeoxygenase‐1, malondialdehyde‐modified protein, and OH8dG in both SALS and FALS spinal cord. These studies therefore provide further evidence that oxidative damage may play a role in the pathogenesis of neuronal degeneration in both SALS and FALS.

[1]  M. Pericak-Vance,et al.  Amyotrophic lateral sclerosis and structural defects in Cu,Zn superoxide dismutase. , 1993, Science.

[2]  B. Halliwell,et al.  The measurement and mechanism of lipid peroxidation in biological systems. , 1990, Trends in biochemical sciences.

[3]  S. Sasaki,et al.  Impairment of fast axonal transport in the proximal axons of anterior horn neurons in amyotrophic lateral sclerosis , 1996, Neurology.

[4]  K. Sakimura,et al.  A novel mutation in Cu/Zn superoxide dismutase gene in Japanese familial amyotrophic lateral sclerosis. , 1994, Biochemical and biophysical research communications.

[5]  J. Slade,et al.  Familial amyotrophic lateral sclerosis with a mutation in exon 4 of the Cu/Zn superoxide dismutase gene: pathological and immunocytochemical changes , 1996, Acta Neuropathologica.

[6]  W. D. Ehmann,et al.  Iron, selenium and glutathione peroxidase activity are elevated in sporadic motor neuron disease , 1994, Neuroscience Letters.

[7]  R. Lanius,et al.  Increased [35S]glutathione binding sites in spinal cords from patients with sporadic amyotrophic lateral sclerosis , 1993, Neuroscience Letters.

[8]  W. Hung,et al.  Intense Superoxide Dismutase‐1 Immunoreactivity in Intracytoplasmic Hyaline Inclusions of Familial Amyotrophic Lateral Sclerosis with Posterior Column Involvement , 1996, Journal of neuropathology and experimental neurology.

[9]  P. Mecocci,et al.  Oxidative damage to mitochondrial DNA shows marked age‐dependent increases in human brain , 1993, Annals of neurology.

[10]  L. Kurland,et al.  Familial adult motor neuron disease: amyotrophic lateral sclerosis , 1986, Neurology.

[11]  F. Joó,et al.  Ultrastructural evidence for altered calcium in motor nerve terminals in amyotrophc lateral sclerosis , 1996, Annals of neurology.

[12]  J. Phillis.  A “radical” view of cerebral ischemic injury , 1994, Progress in Neurobiology.

[13]  P. Ince,et al.  Oxidative damage to protein in sporadic motor neuron disease spinal cord , 1995, Annals of neurology.

[14]  H. Horvitz,et al.  Superoxide Dismutase Concentration and Activity in Familial Amyotrophic Lateral Sclerosis , 1995, Journal of neurochemistry.

[15]  Robert H. Brown,et al.  Amyotrophic lateral sclerosis: Recent insights from genetics and transgenic mice , 1995, Cell.

[16]  M. Carson,et al.  ALS, SOD and peroxynitrite , 1993, Nature.

[17]  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.

[18]  J. Aznar,et al.  Determination of plasma malondialdehyde-like material and its clinical application in stroke patients. , 1980, Journal of clinical pathology.

[19]  D. Borchelt,et al.  Superoxide dismutase 1 with mutations linked to familial amyotrophic lateral sclerosis possesses significant activity. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[20]  W. Paschen,et al.  Hemeoxygenase expression after reversible ischemia of rat brain , 1994, Neuroscience Letters.

[21]  J. Haines,et al.  Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis , 1993, Nature.

[22]  A. Clark,et al.  SOD1 mutation is associated with accumulation of neurofilaments in amyotrophic lateral sclerosis. , 1996, Annals of neurology.

[23]  G. Rosoklija,et al.  Brain superoxide dismutase, catalase, and glutathione peroxidase activities in amyotrophic lateral sclerosis , 1996, Annals of neurology.

[24]  L. Noble,et al.  Induction of heme oxygenase-1 (HO-1) after traumatic brain injury in the rat , 1995, Neuroscience Letters.

[25]  D. McAdoo,et al.  Hydroxyl Radicals Generated In Vivo Kill Neurons in the Rat Spinal Cord: Electrophysiological, Histological, and Neurochemical Results , 1994, Journal of neurochemistry.

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

[27]  E. Hall,et al.  Central nervous system trauma and stroke. II. Physiological and pharmacological evidence for involvement of oxygen radicals and lipid peroxidation. , 1989, Free radical biology & medicine.

[28]  B. Halliwell,et al.  Lipid peroxidation: its mechanism, measurement, and significance. , 1993, The American journal of clinical nutrition.

[29]  M. Dizdaroglu.  Chemical determination of free radical-induced damage to DNA. , 1991, Free radical biology & medicine.

[30]  Elsdon Storey,et al.  Excitotoxin Lesions in Primates as a Model for Huntington's Disease: Histopathologic and Neurochemical Characterization , 1993, Experimental Neurology.

[31]  Robert H. Brown,et al.  Superoxide Dismutase Activity, Oxidative Damage, and Mitochondrial Energy Metabolism in Familial and Sporadic Amyotrophic Lateral Sclerosis , 1993, Journal of neurochemistry.

[32]  Y. Itoyama,et al.  Mild ALS in Japan associated with novel SOD mutation , 1993, Nature Genetics.

[33]  W. Markesbery,et al.  Excess brain protein oxidation and enzyme dysfunction in normal aging and in Alzheimer disease. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[34]  S. M. Chou,et al.  Colocalization of NOS and SOD1 in neurofilament accumulation within motor neurons of amyotrophic lateral sclerosis: an immunohistochemical study , 1996, Journal of Chemical Neuroanatomy.

[35]  P. Weinstein,et al.  Heme oxygenase-1 (HO-1) protein induction in rat brain following focal ischemia. , 1996, Brain research. Molecular brain research.

[36]  J. Haines,et al.  Linkage of a gene causing familial amyotrophic lateral sclerosis to chromosome 21 and evidence of genetic-locus heterogeneity. , 1991, The New England journal of medicine.

[37]  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.

[38]  M. Michikawa,et al.  Oxygen radical‐induced neurotoxicity in spinal cord neuron cultures , 1994, Journal of neuroscience research.

[39]  J. Morrison,et al.  Transgenic mice expressing an altered murine superoxide dismutase gene provide an animal model of amyotrophic lateral sclerosis. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

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

[41]  A. Belli,et al.  MDA, oxypurines, and nucleosides relate to reperfusion in short-term incomplete cerebral ischemia in the rat. , 1992, Free radical biology & medicine.

[42]  B. Dwyer,et al.  Differential expression of heme oxygenase-1 in cultured cortical neurons and astrocytes determined by the aid of a new heme oxygenase antibody. Response to oxidative stress. , 1995, Brain research. Molecular brain research.

[43]  E. Stopa,et al.  Expression of heme oxygenase‐1 in the senescent and alzheimer‐diseased brain , 1995, Annals of neurology.

[44]  J. Lai,et al.  Preparation of synaptic and nonsynaptic mitochondria from mammalian brain. , 1979, Methods in enzymology.

[45]  Y. Itoyama,et al.  Induction of nitrotyrosine-like immunoreactivity in the lower motor neuron of amyotrophic lateral sclerosis , 1995, Neuroscience Letters.

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

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

[48]  Guy A. Rouleau,et al.  SOD1 mutation is assosiated with accumulation of neurofilaments in amyotrophic lateral scelaries , 1996 .

[49]  E. Stadtman,et al.  Determination of carbonyl content in oxidatively modified proteins. , 1990, Methods in enzymology.

[50]  P. Leigh,et al.  Cu/Zn superoxide dismutase gene mutations in amyotrophic lateral sclerosis: correlation between genotype and clinical features. , 1996, Journal of neurology, neurosurgery, and psychiatry.

[51]  W. Bradley,et al.  Amyotrophc Lateral Sclerosis: Part 1. Clinical Features, Pathology, and E h c d Issues in Management* , 2004 .

[52]  D. Borchelt,et al.  An adverse property of a familial ALS-linked SOD1 mutation causes motor neuron disease characterized by vacuolar degeneration of mitochondria , 1995, Neuron.

[53]  D. Troost,et al.  Enhanced superoxide dismutase-2 immunoreactivity of astrocytes and occasional neurons in amyotrophic lateral sclerosis , 1996, Journal of the Neurological Sciences.

[54]  S. Chirico,et al.  High-performance liquid chromatography-based thiobarbituric acid tests. , 1994, Methods in enzymology.

[55]  J. Troncoso,et al.  Metal-catalyzed oxidation of bovine neurofilaments in vitro. , 1995, Free radical biology & medicine.

[56]  M. Smith,et al.  Glycoxidation and oxidative stress in Parkinson disease and diffuse Lewy body disease , 1996, Brain Research.

[57]  S. Przedborski,et al.  Blood superoxide dismutase, catalase and glutathione peroxidase activities in familial and sporadic amyotrophic lateral sclerosis. , 1996, Neurodegeneration : a journal for neurodegenerative disorders, neuroprotection, and neuroregeneration.