title: Oxidation-induced misfolding and aggregation of superoxide dismutase and its implications for amyotrophic lateral sclerosis.
abstract: The presence of intracellular aggregates that contain Cu/Zn superoxide dismutase (SOD1) in spinal cord motor neurons is a pathological hallmark of amyotrophic lateral sclerosis (ALS). Although SOD1 is abundant in all cells, its half-life in motor neurons far exceeds that in any other cell type. On the basis of the premise that the long half-life of the protein increases the potential for oxidative damage, we investigated the effects of oxidation on misfolding/aggregation of SOD1 and ALS-associated SOD1 mutants. Zinc-deficient wild-type SOD1 and SOD1 mutants were extremely prone to form visible aggregates upon oxidation as compared with wild-type holo-protein. Oxidation of select histidine residues that bind metals in the active site mediates SOD1 aggregation. Our results provide a plausible model to explain the accumulation of SOD1 aggregates in motor neurons affected in ALS.
mesh_terms: D000596:Amino Acids / Q000378:metabolism; D000690:Amyotrophic Lateral Sclerosis / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism; D052160:Benzothiazoles; D001665:Binding Sites; D002853:Chromatography, Liquid; D002942:Circular Dichroism; D004912:Erythrocytes / Q000201:enzymology; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008027:Light; D018625:Microscopy, Atomic Force; D008958:Models, Molecular; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D009474:Neurons / Q000378:metabolism; D010100:Oxygen / Q000378:metabolism; D011485:Protein Binding; D017510:Protein Folding; D012542:Scattering, Radiation; D013482:Superoxide Dismutase / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D013844:Thiazoles / Q000378:metabolism; D015032:Zinc / Q000378:metabolism
chemical_list: D000596:Amino Acids; D052160:Benzothiazoles; D013844:Thiazoles; C009462:thioflavin T; D013482:Superoxide Dismutase; D015032:Zinc; D010100:Oxygen