Structure, folding, and misfolding of Cu,Zn superoxide dismutase in amyotrophic lateral sclerosis.

Fourteen years after the discovery that mutations in Cu, Zn superoxide dismutase (SOD1) cause a subset of familial amyotrophic lateral sclerosis (fALS), the mechanism by which mutant SOD1 exerts toxicity remains unknown. The two principle hypotheses are (a) oxidative damage stemming from aberrant SOD1 redox chemistry, and (b) misfolding of the mutant protein. Here we review the structure and function of wild-type SOD1, as well as the changes to the structure and function in mutant SOD1. The relative merits of the two hypotheses are compared and a common unifying principle is outlined. Lastly, the potential for therapies targeting SOD1 misfolding is discussed.

[1]  M. Gurney,et al.  Presence of Cu/Zn superoxide dismutase (SOD) immunoreactivity in neuronal hyaline inclusions in spinal cords from mice carrying a transgene for Gly93Ala mutant human Cu/Zn SOD , 1998, Acta Neuropathologica.

[2]  E. Gratton,et al.  Fluorescence lifetime distributions in human superoxide dismutase. Effect of temperature and denaturation. , 1990, Biophysical journal.

[3]  J. Thompson,et al.  Decreased Zinc Affinity of Amyotrophic Lateral Sclerosis‐Associated Superoxide Dismutase Mutants Leads to Enhanced Catalysis of Tyrosine Nitration by Peroxynitrite , 1997, Journal of neurochemistry.

[4]  K. Beyreuther,et al.  Alzheimer's disease: molecular concepts and therapeutic targets , 2001, Naturwissenschaften.

[5]  A. Nersissian,et al.  Loss of in Vitro Metal Ion Binding Specificity in Mutant Copper-Zinc Superoxide Dismutases Associated with Familial Amyotrophic Lateral Sclerosis* , 2000, The Journal of Biological Chemistry.

[6]  M. Ferraroni,et al.  The crystal structure of the monomeric human SOD mutant F50E/G51E/E133Q at atomic resolution. The enzyme mechanism revisited. , 1999, Journal of molecular biology.

[7]  J. Valentine,et al.  Mechanisms for activating Cu- and Zn-containing superoxide dismutase in the absence of the CCS Cu chaperone. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

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

[9]  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.

[10]  J. Tower.  There's a problem in the furnace. , 2004, Science of aging knowledge environment : SAGE KE.

[11]  J. Crapo,et al.  [41] Preparation and assay of superioxide dismutases , 1978 .

[12]  R. Casareno,et al.  The Copper Chaperone for Superoxide Dismutase* , 1997, The Journal of Biological Chemistry.

[13]  Peter A. Kollman,et al.  Electrostatic recognition between superoxide and copper, zinc superoxide dismutase , 1983, Nature.

[14]  B. Robinson,et al.  Mitochondria, oxygen free radicals, disease and ageing. , 2000, Trends in biochemical sciences.

[15]  A. Desideri,et al.  Dynamics-function correlation in Cu, Zn superoxide dismutase: a spectroscopic and molecular dynamics simulation study. , 2001, Biophysical journal.

[16]  I. Felli,et al.  Direct detection of hydrogen bonds in monomeric superoxide dismutase: biological implications. , 2002, Biochemistry.

[17]  R. Strange,et al.  A critical assessment of the evidence from XAFS and crystallography for the breakage of the imidazolate bridge during catalysis in CuZn superoxide dismutase. , 1997, Structure.

[18]  Peter T Lansbury,et al.  Small-molecule-mediated stabilization of familial amyotrophic lateral sclerosis-linked superoxide dismutase mutants against unfolding and aggregation. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[19]  J. Tainer,et al.  Insights into Lou Gehrig's disease from the structure and instability of the A4V mutant of human Cu,Zn superoxide dismutase. , 2002, Journal of molecular biology.

[20]  N. Shibata,et al.  Immunohistochemical study on superoxide dismutases in spinal cords from autopsied patients with amyotrophic lateral sclerosis. , 1996, Developmental neuroscience.

[21]  J. Rumfeldt,et al.  Mechanism and thermodynamics of guanidinium chloride-induced denaturation of ALS-associated mutant Cu,Zn superoxide dismutases. , 2006, Journal of molecular biology.

[22]  G. Ghadge,et al.  Truncated wild-type SOD1 and FALS-linked mutant SOD1 cause neural cell death in the chick embryo spinal cord , 2006, Neurobiology of Disease.

[23]  J. Richardson,et al.  Determination and analysis of the 2 A-structure of copper, zinc superoxide dismutase. , 1980, Journal of molecular biology.

[24]  D. Borchelt,et al.  Superoxide dismutase is an abundant component in cell bodies, dendrites, and axons of motor neurons and in a subset of other neurons. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[25]  J. Kelly,et al.  The acid-mediated denaturation pathway of transthyretin yields a conformational intermediate that can self-assemble into amyloid. , 1996, Biochemistry.

[26]  N. Blough,et al.  Reaction of superoxide with nitric oxide to form peroxonitrite in alkaline aqueous solution , 1985 .

[27]  A. Holmgren,et al.  Folding of human superoxide dismutase: disulfide reduction prevents dimerization and produces marginally stable monomers. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[28]  A. Lamb,et al.  Heterodimeric structure of superoxide dismutase in complex with its metallochaperone , 2001, Nature Structural Biology.

[29]  P. Eisenberger,et al.  Superoxide dismutase, a study of the electronic properties of the copper and zinc by X-ray absorption spectroscopy. , 1978, Biochemistry.

[30]  The solution structure of a monomeric, reduced form of human copper,zinc superoxide dismutase bearing the same charge as the native protein , 1999, JBIC Journal of Biological Inorganic Chemistry.

[31]  Michael A Hough,et al.  Variable metallation of human superoxide dismutase: atomic resolution crystal structures of Cu-Zn, Zn-Zn and as-isolated wild-type enzymes. , 2006, Journal of molecular biology.

[32]  E. Stadtman,et al.  A Familial Amyotrophic Lateral Sclerosis-associated A4V Cu,Zn-Superoxide Dismutase Mutant Has a Lower Km for Hydrogen Peroxide , 1997, The Journal of Biological Chemistry.

[33]  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.

[34]  John A. Tainer,et al.  Structure and mechanism of copper, zinc superoxide dismutase , 1983, Nature.

[35]  A. Amadei,et al.  The essential dynamics of Cu, Zn superoxide dismutase: suggestion of intersubunit communication. , 1997, Biophysical journal.

[36]  D. Eisenberg,et al.  A structure-based mechanism for copper-zinc superoxide dismutase. , 1999, Biochemistry.

[37]  Robert H. Brown,et al.  An intersubunit disulfide bond prevents in vitro aggregation of a superoxide dismutase-1 mutant linked to familial amytrophic lateral sclerosis. , 2004, Biochemistry.

[38]  E. Gratton,et al.  Denaturation of human Cu/Zn superoxide dismutase by guanidine hydrochloride: a dynamic fluorescence study. , 1992, Biochemistry.

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

[40]  J. Beckman,et al.  Hydrogen peroxide damages the zinc-binding site of zinc-deficient Cu,Zn superoxide dismutase. , 2001, Archives of biochemistry and biophysics.

[41]  J. Wood,et al.  Protein aggregation in motor neurone disorders , 2003, Neuropathology and applied neurobiology.

[42]  A. Chakrabartty,et al.  Oxidation-induced Misfolding and Aggregation of Superoxide Dismutase and Its Implications for Amyotrophic Lateral Sclerosis* , 2002, The Journal of Biological Chemistry.

[43]  A. Desideri,et al.  Role of the Dimeric Structure in Cu,Zn Superoxide Dismutase , 1998, The Journal of Biological Chemistry.

[44]  I. Fridovich,et al.  On the stability of bovine superoxide dismutase. The effects of metals. , 1973, The Journal of biological chemistry.

[45]  E. Getzoff,et al.  Faster superoxide dismutase mutants designed by enhancing electrostatic guidance , 1992, Nature.

[46]  Marco Di Benedetto,et al.  Solution structure of reduced monomeric Q133M2 copper, zinc superoxide dismutase (SOD). Why is SOD a dimeric enzyme?. , 1998, Biochemistry.

[47]  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.

[48]  J. Richardson,et al.  Natural β-sheet proteins use negative design to avoid edge-to-edge aggregation , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[49]  I. Fridovich,et al.  Examination of the role of arginine-143 in the human copper and zinc superoxide dismutase by site-specific mutagenesis. , 1987, The Journal of biological chemistry.

[50]  I. Bertini,et al.  A characterization of copper/zinc superoxide dismutase mutants at position 124. Zinc-deficient proteins. , 1991, European journal of biochemistry.

[51]  A. Tiwari,et al.  Familial Amyotrophic Lateral Sclerosis Mutants of Copper/Zinc Superoxide Dismutase Are Susceptible to Disulfide Reduction* , 2003, The Journal of Biological Chemistry.

[52]  Steven M. Johnson,et al.  Kinetic stabilization of an oligomeric protein by a single ligand binding event. , 2005, Journal of the American Chemical Society.

[53]  T. O’Halloran,et al.  Oxygen and the copper chaperone CCS regulate posttranslational activation of Cu,Zn superoxide dismutase. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[54]  S. Khare,et al.  Sequence and structural determinants of Cu, Zn superoxide dismutase aggregation , 2005, Proteins.

[55]  W. Colón,et al.  Modification of cysteine 111 in Cu/Zn superoxide dismutase results in altered spectroscopic and biophysical properties , 2004, Protein science : a publication of the Protein Society.

[56]  I. Bertini,et al.  The Unusually Stable Quaternary Structure of Human Cu,Zn-Superoxide Dismutase 1 Is Controlled by Both Metal Occupancy and Disulfide Status* , 2004, Journal of Biological Chemistry.

[57]  D. Price,et al.  Elevated free nitrotyrosine levels, but not protein-bound nitrotyrosine or hydroxyl radicals, throughout amyotrophic lateral sclerosis (ALS)-like disease implicate tyrosine nitration as an aberrant in vivo property of one familial ALS-linked superoxide dismutase 1 mutant. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[58]  D C Richardson,et al.  Similarity of three-dimensional structure between the immunoglobulin domain and the copper, zinc superoxide dismutase subunit. , 1976, Journal of molecular biology.

[59]  I. Bertini,et al.  Synthesis and characterization of a monomeric mutant Cu/Zn superoxide dismutase with partially reconstituted enzymic activity. , 1995, European journal of biochemistry.

[60]  V. Bindokas,et al.  No correlation between aggregates of Cu/Zn superoxide dismutase and cell death in familial amyotrophic lateral sclerosis , 2002, Journal of neurochemistry.

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

[62]  S. Jewett,et al.  A new look at a time-worn system: oxidation of CuZn-SOD by H2O2. , 1999, Free radical biology & medicine.

[63]  M. Gurney,et al.  Protein Oxidative Damage in a Transgenic Mouse Model of Familial Amyotrophic Lateral Sclerosis , 1998, Journal of neurochemistry.

[64]  John A Tainer,et al.  ALS mutants of human superoxide dismutase form fibrous aggregates via framework destabilization. , 2003, Journal of molecular biology.

[65]  K. Uchida,et al.  Identification of oxidized histidine generated at the active site of Cu,Zn-superoxide dismutase exposed to H2O2. Selective generation of 2-oxo-histidine at the histidine 118. , 1994, The Journal of biological chemistry.

[66]  S. Antonyuk,et al.  Structural consequences of the familial amyotrophic lateral sclerosis SOD1 mutant His46Arg , 2005, Protein science : a publication of the Protein Society.

[67]  E. Stadtman,et al.  Copper, zinc superoxide dismutase catalyzes hydroxyl radical production from hydrogen peroxide. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[68]  D. Borchelt,et al.  Variation in the biochemical/biophysical properties of mutant superoxide dismutase 1 enzymes and the rate of disease progression in familial amyotrophic lateral sclerosis kindreds. , 1999, Human molecular genetics.

[69]  J. Berg,et al.  Principles Of Bioinorganic Chemistry , 1994 .

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

[71]  L. T. Hall,et al.  X-ray crystallographic and analytical ultracentrifugation analyses of truncated and full-length yeast copper chaperones for SOD (LYS7): a dimer-dimer model of LYS7-SOD association and copper delivery. , 2000, Biochemistry.

[72]  J. Gitlin,et al.  Mechanisms of Biosynthesis of Mammalian Copper/Zinc Superoxide Dismutase* , 2003, Journal of Biological Chemistry.

[73]  Peter M Andersen,et al.  Systematically perturbed folding patterns of amyotrophic lateral sclerosis (ALS)-associated SOD1 mutants. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[74]  I. Fridovich,et al.  Superoxide dismutase. An enzymic function for erythrocuprein (hemocuprein). , 1969, The Journal of biological chemistry.

[75]  M. Conaway,et al.  Accelerated S-Nitrosothiol Breakdown by Amyotrophic Lateral Sclerosis Mutant Copper,Zinc-Superoxide Dismutase* , 2001, The Journal of Biological Chemistry.

[76]  J. Kelly,et al.  Prevention of Transthyretin Amyloid Disease by Changing Protein Misfolding Energetics , 2003, Science.

[77]  M. Beal,et al.  Motor neurons in Cu/Zn superoxide dismutase-deficient mice develop normally but exhibit enhanced cell death after axonal injury , 1996, Nature Genetics.

[78]  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.

[79]  T. Gillingwater,et al.  A mutation in the vesicle-trafficking protein VAPB causes late-onset spinal muscular atrophy and amyotrophic lateral sclerosis. , 2004, American journal of human genetics.

[80]  D. Borchelt,et al.  ALS-Linked SOD1 Mutant G85R Mediates Damage to Astrocytes and Promotes Rapidly Progressive Disease with SOD1-Containing Inclusions , 1997, Neuron.

[81]  D. Borchelt,et al.  Copper-binding-site-null SOD1 causes ALS in transgenic mice: aggregates of non-native SOD1 delineate a common feature. , 2003, Human molecular genetics.

[82]  W. Colón,et al.  Cu/Zn superoxide dismutase can form pore-like structures. , 2003, Biochemical and biophysical research communications.

[83]  J. Rumfeldt,et al.  Calorimetric Analysis of Thermodynamic Stability and Aggregation for Apo and Holo Amyotrophic Lateral Sclerosis-associated Gly-93 Mutants of Superoxide Dismutase* , 2006, Journal of Biological Chemistry.

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

[85]  Michael A Hough,et al.  The structure of holo and metal-deficient wild-type human Cu, Zn superoxide dismutase and its relevance to familial amyotrophic lateral sclerosis. , 2003, Journal of molecular biology.

[86]  I. Fridovich,et al.  Copper- and Zinc-containing Superoxide Dismutase Can Act as a Superoxide Reductase and a Superoxide Oxidase* , 2000, The Journal of Biological Chemistry.

[87]  L. Barbeito,et al.  Induction of motor neuron apoptosis by free 3‐nitro‐l‐tyrosine , 2004, Journal of neurochemistry.

[88]  I. Bertini,et al.  Dynamic properties of the G93A mutant of copper-zinc superoxide dismutase as detected by NMR spectroscopy: implications for the pathology of familial amyotrophic lateral sclerosis. , 2003, Biochemistry.

[89]  T. O’Halloran,et al.  Oxygen‐induced maturation of SOD1: a key role for disulfide formation by the copper chaperone CCS , 2004, The EMBO journal.

[90]  I. Fridovich,et al.  On the role of bicarbonate in peroxidations catalyzed by Cu,Zn superoxide dismutase. , 1999, Free radical biology & medicine.

[91]  A. Mclachlan,et al.  Repeated folding pattern in copper–zinc superoxide dismutase , 1980, Nature.

[92]  N. Guex,et al.  SWISS‐MODEL and the Swiss‐Pdb Viewer: An environment for comparative protein modeling , 1997, Electrophoresis.

[93]  Robert H. Brown,et al.  Decreased Metallation and Activity in Subsets of Mutant Superoxide Dismutases Associated with Familial Amyotrophic Lateral Sclerosis* 210 , 2002, The Journal of Biological Chemistry.

[94]  W. Hagen,et al.  On the reduction potentials of Fe and Cu-Zn containing superoxide dismutases. , 1995, Biochimica et biophysica acta.

[95]  D. Borchelt,et al.  Superoxide Dismutase 1 Subunits with Mutations Linked to Familial Amyotrophic Lateral Sclerosis Do Not Affect Wild-type Subunit Function (*) , 1995, The Journal of Biological Chemistry.

[96]  J. Rumfeldt,et al.  Cu/Zn superoxide dismutase mutants associated with amyotrophic lateral sclerosis show enhanced formation of aggregates in vitro , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[97]  A Hofman,et al.  Genetic epidemiology of amyotrophic lateral sclerosis , 2003, Clinical genetics.

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

[99]  Masaaki Matsuoka,et al.  S-nitrosothiol depletion in amyotrophic lateral sclerosis , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[100]  S. Ennis,et al.  ANG mutations segregate with familial and 'sporadic' amyotrophic lateral sclerosis , 2006, Nature Genetics.

[101]  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.

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

[103]  R. Morimoto,et al.  Huntingtin and Mutant SOD1 Form Aggregate Structures with Distinct Molecular Properties in Human Cells* , 2006, Journal of Biological Chemistry.

[104]  T. O’Halloran,et al.  Undetectable intracellular free copper: the requirement of a copper chaperone for superoxide dismutase. , 1999, Science.

[105]  Robert H. Brown,et al.  Familial Amyotrophic Lateral Sclerosis-associated Mutations Decrease the Thermal Stability of Distinctly Metallated Species of Human Copper/Zinc Superoxide Dismutase* , 2002, The Journal of Biological Chemistry.

[106]  B. Freeman,et al.  Apparent hydroxyl radical production by peroxynitrite: implications for endothelial injury from nitric oxide and superoxide. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[107]  I. Fridovich,et al.  Superoxide and nitric oxide: consequences of varying rates of production and consumption: a theoretical treatment. , 2002, Free radical biology & medicine.

[108]  Nikolay V Dokholyan,et al.  Common dynamical signatures of familial amyotrophic lateral sclerosis-associated structurally diverse Cu, Zn superoxide dismutase mutants. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[109]  A. Bush.  Is ALS caused by an altered oxidative activity of mutant superoxide dismutase? , 2002, Nature Neuroscience.

[110]  E. Gratton,et al.  Molten globule monomers in human superoxide dismutase. , 1993, Biophysical chemistry.

[111]  I. Fridovich,et al.  CO2, not HCO3-, facilitates oxidations by Cu,Zn superoxide dismutase plus H2O2. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[112]  C. Outten,et al.  Femtomolar Sensitivity of Metalloregulatory Proteins Controlling Zinc Homeostasis , 2001, Science.

[113]  Corinne J. Smith,et al.  Natively unfolded domains in endocytosis: hooks, lines and linkers , 2004, EMBO reports.

[114]  Z. Liao,et al.  A study on superoxide dismutase activity of some model compounds. , 1994, Journal of inorganic biochemistry.

[115]  Nikolay V Dokholyan,et al.  The rate and equilibrium constants for a multistep reaction sequence for the aggregation of superoxide dismutase in amyotrophic lateral sclerosis. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[116]  J. Lepock,et al.  Structural analyses of various Cu2+, Zn2+-superoxide dismutases by differential scanning calorimetry and Raman spectroscopy. , 1985, Archives of biochemistry and biophysics.

[117]  L. Tibell,et al.  Common denominator of Cu/Zn superoxide dismutase mutants associated with amyotrophic lateral sclerosis: Decreased stability of the apo state , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[118]  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.

[119]  T. O’Halloran,et al.  Amyotrophic Lateral Sclerosis Mutations Have the Greatest Destabilizing Effect on the Apo- and Reduced Form of SOD1, Leading to Unfolding and Oxidative Aggregation* , 2005, Journal of Biological Chemistry.

[120]  J. Kelly,et al.  FAP mutations destabilize transthyretin facilitating conformational changes required for amyloid formation. , 2007, Ciba Foundation symposium.

[121]  M. Boissinot,et al.  Function of the Greek key connection analysed using circular permutants of superoxide dismutase , 1997, The EMBO journal.

[122]  I. Fridovich,et al.  A direct demonstration of the catalytic action of superoxide dismutase through the use of pulse radiolysis. , 1972, The Journal of biological chemistry.

[123]  Jennifer Stine Elam,et al.  Amyloid-like filaments and water-filled nanotubes formed by SOD1 mutant proteins linked to familial ALS , 2003, Nature Structural Biology.

[124]  A J Olson,et al.  Structural symmetry and protein function. , 2000, Annual review of biophysics and biomolecular structure.

[125]  G. Cartwright,et al.  Studies on copper metabolism. XXVII. The isolation and properties of an erythrocyte cuproprotein (erythrocuprein). , 1959, The Journal of biological chemistry.

[126]  J Günter Grossmann,et al.  Dimer destabilization in superoxide dismutase may result in disease-causing properties: structures of motor neuron disease mutants. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[127]  Lewis E. Kay,et al.  Protein dynamics from NMR , 1998, Nature Structural Biology.

[128]  A. Rosato,et al.  Backbone dynamics of human Cu,Zn superoxide dismutase and of its monomeric F50E/G51E/E133Q mutant: the influence of dimerization on mobility and function. , 2000, Biochemistry.

[129]  B. Kalyanaraman,et al.  Bicarbonate Enhances the Peroxidase Activity of Cu,Zn-Superoxide Dismutase , 1999, The Journal of Biological Chemistry.

[130]  L. Dugan,et al.  Rapid microplate assay for superoxide scavenging efficiency , 2000, Journal of Neuroscience Methods.

[131]  S. Cuzzocrea,et al.  A nonpeptidyl mimic of superoxide dismutase with therapeutic activity in rats. , 1999, Science.

[132]  J. Valentine,et al.  Copper-zinc superoxide dismutase and amyotrophic lateral sclerosis. , 2005, Annual review of biochemistry.

[133]  L. T. Jensen,et al.  Activation of CuZn Superoxide Dismutases from Caenorhabditis elegans Does Not Require the Copper Chaperone CCS* , 2005, Journal of Biological Chemistry.

[134]  Bryan F. Shaw,et al.  Destabilization of apoprotein is insufficient to explain Cu,Zn-superoxide dismutase-linked ALS pathogenesis. , 2005, Proceedings of the National Academy of Sciences of the United States of America.