title: Modulation of mutant superoxide dismutase 1 aggregation by co-expression of wild-type enzyme.
abstract: Mutations in superoxide dismutase 1 (SOD1, EC 1.15.1.1) cause familial amyotrophic lateral sclerosis; with aggregated forms of mutant protein accumulating in spinal cord tissues of transgenic mouse models and human patients. Mice over-expressing wild-type human SOD1 (WT hSOD1) do not develop amyotrophic lateral sclerosis-like disease, but co-expression of WT enzyme at high levels with mutant SOD1 accelerates the onset of motor neuron disease compared with mice expressing mutant hSOD1 alone. Spinal cords of mice expressing both proteins contain aggregated forms of mutant protein and, in some cases, evidence of co-aggregation of WT hSOD1 enzyme. In the present study, we used a cell culture model of mutant SOD1 aggregation to examine how the presence of WT SOD1 affects mutant protein aggregation, finding that co-expression of WT SOD1, hSOD1 or mouse SOD1, delayed the formation of mutant hSOD1 aggregates; in essence appearing to slow the aggregation rate. In some combinations of WT and mutant hSOD1 co-expression, the aggregates that did eventually form appeared to contain WT hSOD1 protein. However, WT mouse SOD1 did not co-aggregate with mutant hSOD1 despite displaying a similar ability to slow mutant hSOD1 aggregation. Together, these studies indicate that WT SOD1 (human or mouse), when expressed at levels equivalent to the mutant protein, modulates the aggregation of mutant SOD1.
authors.affiliation: Department of Neuroscience, McKnight Brain Institute, University of Florida, Gainesville, USA.
authors.forename: Mercedes
authors.initials: M
authors.lastname: Prudencio
authors.forename: Armando
authors.initials: A
authors.lastname: Durazo
authors.forename: Julian P
authors.initials: JP
authors.lastname: Whitelegge
authors.forename: David R
authors.initials: DR
authors.lastname: Borchelt
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology; D000818:Animals; D016923:Cell Death / Q000235:genetics; D002460:Cell Line; D015971:Gene Expression Regulation, Enzymologic / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006801:Humans; D002479:Inclusion Bodies / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D046911:Macromolecular Substances / Q000378:metabolism; D051379:Mice; D009046:Motor Neurons / Q000201:enzymology* / Q000473:pathology; D009154:Mutation / Q000235:genetics; D009410:Nerve Degeneration / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology; D013045:Species Specificity; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism*; D000072105:Superoxide Dismutase-1
chemical_list: D046911:Macromolecular Substances; C000606290:SOD1 protein, human; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1