Oxidative stress and metal content in blood and cerebrospinal fluid of amyotrophic lateral sclerosis patients with and without a Cu, Zn-superoxide dismutase mutation

Ihara, Yoshito; Nobukuni, Keigo; Takata, Hiroshi; Hayabara, Toshiyuki

doi:10.1179/016164105x18430

Cited by 114 publications

(75 citation statements)

References 8 publications

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“…Markers for protein and lipid oxidation were detected in motor neurons, reactive astrocytes, and microglia or macrophages (Shibata et al 2001). Cerebrospinal fluid samples from ALS patients demonstrate increased levels of 8-OHdG (indicative of DNA oxidation), 4-hydroxynonenal (indicative of lipid peroxidation), ascorbate free radical, 3-nitrotyrosine levels and nitrated manganese superoxide dismutase (Smith et al 1998;Tohgi et al 1999;Aoyama et al 2000;Bogdanov et al 2000;Simpson et al 2004;Ihara et al 2005).…”

Section: Discussionmentioning

confidence: 98%

DJ-1 Changes in G93A-SOD1 Transgenic Mice: Implications for Oxidative Stress in ALS

et al. 2008

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Amyotrophic lateral sclerosis (ALS) is a progressive, lethal, neurodegenerative disorder. The causes of ALS are still obscure. Accumulating evidence supports the hypothesis that oxidative stress and mitochondrial dysfunction can be implicated in ALS pathogenesis. DJ-1 plays an important role in the oxidative stress response. The aim of this study was to discover whether there are changes in DJ-1 expression or in DJ-1-oxidized isoforms in an animal model of ALS. We used mutant SOD1(G93A) transgenic mice, a commonly used animal model for ALS. Upregulation of DJ-1 mRNA and protein levels were identified in the brains and spinal cords of SOD1(G93A) transgenic mice as compared to wild-type controls, evident from an early disease stage. Furthermore, an increase in DJ-1 acidic isoforms was detected, implying that there are more oxidized forms of DJ-1 in the CNS of SOD1(G93A) mice. This is the first report of possible involvement of DJ-1 in ALS. Since DJ-1 has a protective role against oxidative stress, it may suggest a possible therapeutic target in ALS.

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Section: Discussionmentioning

confidence: 98%

DJ-1 Changes in G93A-SOD1 Transgenic Mice: Implications for Oxidative Stress in ALS

et al. 2008

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“…Elevated levels of 8-OHdG (205) and HNE (355) were observed in CSF samples from ALS patients. Transgenic mouse and cell culture models of ALS showed a similar pattern of oxidation that was confirmed by the findings of increased levels of oxidative damage to protein, lipid, and DNA observed in the human disease (15,145).…”

Section: G93amentioning

confidence: 99%

Redox Proteomics in Selected Neurodegenerative Disorders: From Its Infancy to Future Applications

Butterfield

Perluigi

Reed

et al. 2012

Antioxidants & Redox Signaling

157

142

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Several studies demonstrated that oxidative damage is a characteristic feature of many neurodegenerative diseases. The accumulation of oxidatively modified proteins may disrupt cellular functions by affecting protein expression, protein turnover, cell signaling, and induction of apoptosis and necrosis, suggesting that protein oxidation could have both physiological and pathological significance. For nearly two decades, our laboratory focused particular attention on studying oxidative damage of proteins and how their chemical modifications induced by reactive oxygen species/reactive nitrogen species correlate with pathology, biochemical alterations, and clinical presentations of Alzheimer's disease. This comprehensive article outlines basic knowledge of oxidative modification of proteins and lipids, followed by the principles of redox proteomics analysis, which also involve recent advances of mass spectrometry technology, and its application to selected age-related neurodegenerative diseases. Redox proteomics results obtained in different diseases and animal models thereof may provide new insights into the main mechanisms involved in the pathogenesis and progression of oxidativestress-related neurodegenerative disorders. Redox proteomics can be considered a multifaceted approach that has the potential to provide insights into the molecular mechanisms of a disease, to find disease markers, as well as to identify potential targets for drug therapy. Considering the importance of a better understanding of the cause/effect of protein dysfunction in the pathogenesis and progression of neurodegenerative disorders, this article provides an overview of the intrinsic power of the redox proteomics approach together with the most significant results obtained by our laboratory and others during almost 10 years of research on neurodegenerative disorders since we initiated the field of redox proteomics. Antioxid. Redox Signal. 17, 1610-1655.

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“…Before the discovery linking SOD1 and ALS, epidemiological studies on ALS suggested that exposure to metallic trace elements was a significant factor among many other environmental factors such as viruses, strenuous exercise, and excitotoxic chemicals that may have a role in ALS etiology (4 -6). Studies on exposure to and tissue accumulation of metallic elements in ALS patients show a correlative yet unspecified role for many metals including copper and zinc in SOD1-related ALS (7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19). Over the years, a number of hypotheses relating metal toxicity to ALS have been proposed.…”

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confidence: 99%

Copper and Zinc Metallation Status of Copper-Zinc Superoxide Dismutase from Amyotrophic Lateral Sclerosis Transgenic Mice

Lelie

Liba

Bourassa

et al. 2011

Journal of Biological Chemistry

120

138

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Mutations in the metalloenzyme copper-zinc superoxide dismutase (SOD1) cause one form of familial amyotrophic lateral sclerosis (ALS), and metals are suspected to play a pivotal role in ALS pathology. To learn more about metals in ALS, we determined the metallation states of human wild-type or mutant (G37R, G93A, and H46R/H48Q) SOD1 proteins from SOD1-ALS transgenic mice spinal cords. SOD1 was gently extracted from spinal cord and separated into insoluble (aggregated) and soluble (supernatant) fractions, and then metallation states were determined by HPLC inductively coupled plasma MS. Insoluble SOD1-rich fractions were not enriched in copper and zinc. However, the soluble mutant and WT SOD1s were highly metallated except for the metal-bindingregion mutant H46R/H48Q, which did not bind any copper. Due to the stability conferred by high metallation of G37R and G93A, it is unlikely that these soluble SOD1s are prone to aggregation in vivo, supporting the hypothesis that immature nascent SOD1 is the substrate for aggregation. We also investigated the effect of SOD1 overexpression and disease on metal homeostasis in spinal cord cross-sections of SOD1-ALS mice using synchrotron-based x-ray fluorescence microscopy. In each mouse genotype, except for the H46R/H48Q mouse, we found a redistribution of copper between gray and white matters correlated to areas of high SOD1. Interestingly, a diseasespecific increase of zinc was observed in the white matter for all mutant SOD1 mice. Together these data provide a picture of copper and zinc in the cell as well as highlight the importance of these metals in understanding SOD1-ALS pathology.First described in 1869 by French neurologist Jean-Martin Charcot (1), amyotrophic lateral sclerosis (ALS) 4 is defined by the progressive demise of lower and upper motor neurons leading to the degeneration of muscle tissue and eventual paralysis (2). Familial ALS was linked in 1993 to mutations in the gene that encodes the metalloenzyme copper-zinc, superoxide dismutase (SOD1) (3), and since that time more than 140 different disease-causing mutations have been identified (4). Before the discovery linking SOD1 and ALS, epidemiological studies on ALS suggested that exposure to metallic trace elements was a significant factor among many other environmental factors such as viruses, strenuous exercise, and excitotoxic chemicals that may have a role in ALS etiology (4 -6). Studies on exposure to and tissue accumulation of metallic elements in ALS patients show a correlative yet unspecified role for many metals including copper and zinc in SOD1-related ALS (7-19). Over the years, a number of hypotheses relating metal toxicity to ALS have been proposed. For example, abnormal accumulations of redox-active metal ions such as iron or copper in ALS patients were generally believed to be detrimental due to their ability to mediate oxidative damage through participation in reactions that lead to formation of reactive oxygen species. A more specific hypothesis linking metallation levels of mutant SOD1 to...

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Oxidative stress and metal content in blood and cerebrospinal fluid of amyotrophic lateral sclerosis patients with and without a Cu, Zn-superoxide dismutase mutation

Cited by 114 publications

References 8 publications

DJ-1 Changes in G93A-SOD1 Transgenic Mice: Implications for Oxidative Stress in ALS

DJ-1 Changes in G93A-SOD1 Transgenic Mice: Implications for Oxidative Stress in ALS

Redox Proteomics in Selected Neurodegenerative Disorders: From Its Infancy to Future Applications

Copper and Zinc Metallation Status of Copper-Zinc Superoxide Dismutase from Amyotrophic Lateral Sclerosis Transgenic Mice

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