title: An examination of wild-type SOD1 in modulating the toxicity and aggregation of ALS-associated mutant SOD1.
abstract: Mutations in superoxide dismutase 1 (SOD1) are associated with familial cases of amyotrophic lateral sclerosis (fALS). Studies in transgenic mice have suggested that wild-type (WT) SOD1 can modulate the toxicity of mutant SOD1. In the present study, we demonstrate that the effects of WT SOD1 on the age at which transgenic mice expressing mutant human SOD1 (hSOD1) develop paralysis are influenced by the nature of the ALS mutation and the expression levels of WT hSOD1. We show that regardless of whether WT SOD1 changes the course of disease, both WT and mutant hSOD1 accumulate as detergent-insoluble aggregates in symptomatic mice expressing both proteins. However, using a panel of fluorescently tagged variants of SOD1 in a cell model of mutant SOD1 aggregation, we demonstrate that the interactions between mutant and WT SOD1 in aggregate formation are not simply a co-assembly of mutant and WT proteins. Overall, these data demonstrate that the product of the normal SOD1 allele in fALS has potential to influence the toxicity of mutant SOD1 and that complex interactions with the mutant protein may influence the formation of aggregates and inclusion bodies generated by mutant SOD1.
authors.affiliation: Department of Neuroscience, McKnight Brain Institute, University of Florida, Gainesville, Florida 32610, 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: D000375:Aging / Q000187:drug effects; D000690:Amyotrophic Lateral Sclerosis / Q000150:complications / Q000201:enzymology* / Q000473:pathology*; D000818:Animals; D002478:Cells, Cultured; D003902:Detergents / Q000494:pharmacology; D002479:Inclusion Bodies / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D050505:Mutant Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D010243:Paralysis / Q000150:complications / Q000201:enzymology / Q000473:pathology; D011485:Protein Binding / Q000187:drug effects; D020836:Protein Structure, Quaternary; D012995:Solubility / Q000187:drug effects; D013116:Spinal Cord / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism*; D000072105:Superoxide Dismutase-1
chemical_list: D003902:Detergents; D050505:Mutant Proteins; C000606290:SOD1 protein, human; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1