Amyotrophic lateral sclerosis and structural defects in Cu,Zn superoxide dismutase.

Single-site mutants in the Cu,Zn superoxide dismutase (SOD) gene (SOD1) occur in patients with the fatal neurodegenerative disorder familial amyotrophic lateral sclerosis (FALS). Complete screening of the SOD1 coding region revealed that the mutation Ala4 to Val in exon 1 was the most frequent one; mutations were identified in exons 2, 4, and 5 but not in the active site region formed by exon 3. The 2.4 A crystal structure of human SOD, along with two other SOD structures, established that all 12 observed FALS mutant sites alter conserved interactions critical to the beta-barrel fold and dimer contact, rather than catalysis. Red cells from heterozygotes had less than 50 percent normal SOD activity, consistent with a structurally defective SOD dimer. Thus, defective SOD is linked to motor neuron death and carries implications for understanding and possible treatment of FALS.

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

[2]  I. Fridovich,et al.  Did radicals strike Lou Gehrig? , 1993, Nature.

[3]  S. Antonarakis.  Third International Workshop on Human Chromosome 21. , 1992, Genomics.

[4]  N. Scrutton,et al.  Cooperativity induced by a single mutation at the subunit interface of a dimeric enzyme: glutathione reductase. , 1992, Science.

[5]  G. Borgstahl,et al.  The structure of human mitochondrial manganese superoxide dismutase reveals a novel tetrameric interface of two 4-helix bundles , 1992, Cell.

[6]  B. Singer,et al.  1,N2-ethenodeoxyguanosine: properties and formation in chloroacetaldehyde-treated polynucleotides and DNA. , 1992, Chemical research in toxicology.

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

[8]  J. Tainer,et al.  Atomic structures of wild-type and thermostable mutant recombinant human Cu,Zn superoxide dismutase. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[9]  D. L. Veenstra,et al.  Probing protein stability with unnatural amino acids. , 1992, Science.

[10]  H. Takagi,et al.  Differential regulation of manganese and copper/zinc superoxide dismutases by the facial nerve transection , 1992, Brain Research.

[11]  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.

[12]  M. Nishiyama,et al.  Site-directed mutagenesis of pseudoazurin from Alcaligenes faecalis S-6; Pro80Ala mutant exhibits marked increase in reduction potential. , 1992, Protein engineering.

[13]  B. Matthews,et al.  Response of a protein structure to cavity-creating mutations and its relation to the hydrophobic effect. , 1992, Science.

[14]  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.

[15]  L. Battistin,et al.  Determination of Superoxide Dismutase Activity by the Polarographic Method of Catalytic Currents in the Cerebrospinal Fluid of Aging Brain and Neurologic Degenerative Diseases , 1991, Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine.

[16]  J. Tainer,et al.  Changes in crystallographic structure and thermostability of a Cu,Zn superoxide dismutase mutant resulting from the removal of a buried cysteine. , 1993, The Journal of biological chemistry.

[17]  D. Treiman,et al.  The role of benzodiazepines in the management of status epilepticus , 1990, Neurology.

[18]  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.

[19]  T. Sekiya,et al.  Rapid and sensitive detection of point mutations and DNA polymorphisms using the polymerase chain reaction. , 1989, Genomics.

[20]  T C Terwilliger,et al.  Influence of interior packing and hydrophobicity on the stability of a protein. , 1989, Science.

[21]  M. Pericak-Vance,et al.  Linkage analysis in familial amyotrophic lateral sclerosis , 1989, Neurology.

[22]  L. Oberley,et al.  An assay for superoxide dismutase activity in mammalian tissue homogenates. , 1989, Analytical biochemistry.

[23]  P. Fitzgerald.  MERLOT, an integrated package of computer programs for the determination of crystal structures by molecular replacement , 1988 .

[24]  J. Crapo,et al.  Isolation and characterization of complementary DNAs encoding human manganese‐containing superoxide dismutase , 1988, FEBS letters.

[25]  S. Marklund,et al.  Isolation and sequence of complementary DNA encoding human extracellular superoxide dismutase. , 1987, Proceedings of the National Academy of Sciences of the United States of America.

[26]  I. Fridovich,et al.  alpha, beta-Dihydroxyisovalerate dehydratase. A superoxide-sensitive enzyme. , 1987, The Journal of biological chemistry.

[27]  J. Tainer,et al.  Crystallographic characterization of recombinant human CuZn superoxide dismutase. , 1986, The Journal of biological chemistry.

[28]  I. Fridovich.  Biological effects of the superoxide radical. , 1986, Archives of biochemistry and biophysics.

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

[30]  B. Halliwell,et al.  Oxygen radicals and the nervous system , 1985, Trends in Neurosciences.

[31]  K. Steimer,et al.  Human Cu/Zn superoxide dismutase cDNA: isolation of clones synthesising high levels of active or inactive enzyme from an expression library. , 1985, Nucleic acids research.

[32]  W. Brown,et al.  Chronic progressive myelopathy: Investigation with CSF electrophoresis, evoked potentials, and CT scan , 1979, Annals of neurology.

[33]  I. Fridovich,et al.  Superoxide dismutase: improved assays and an assay applicable to acrylamide gels. , 1971, Analytical biochemistry.

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