title: Heterodimer formation of wild-type and amyotrophic lateral sclerosis-causing mutant Cu/Zn-superoxide dismutase induces toxicity independent of protein aggregation.
abstract: Recent studies provide evidence that wild-type Cu/Zn-superoxide dismutase (SOD1(hWT)) might be an important factor in mutant SOD1-mediated amyotrophic lateral sclerosis (ALS). In order to investigate its functional role in the pathogenesis of ALS, we designed fusion proteins of two SOD1 monomers linked by a polypeptide. We demonstrated that wild-type-like mutants, but not SOD1(G85R) homodimers, as well as mutant heterodimers including SOD1(G85R)-SOD1(hWT) display dismutase activity. Mutant homodimers showed an increased aggregation compared with the corresponding heterodimers in cell cultures and transgenic Caenorhabditis elegans, although SOD1(G85R) heterodimers are more toxic in functional assays. Our data show that (i) toxicity of mutant SOD1 is not correlated to its aggregation potential; (ii) dismutase-inactive mutants form dismutase-active heterodimers with SOD1(hWT); (iii) SOD1(hWT) can be converted to contribute to disease by forming active heterodimers. Therefore, we conclude that toxicity of mutant SOD1 is at least partially mediated through heterodimer formation with SOD1(hWT) in vivo and does not correlate with the aggregation potential of individual mutants.
authors.affiliation: Department of Pathobiochemistry, Medical School, Johannes Gutenberg-University of Mainz, Duesbergweg 6, 55099 Mainz, Germany.
authors.forename: Heidrun
authors.initials: H
authors.lastname: Witan
authors.forename: Andreas
authors.initials: A
authors.lastname: Kern
authors.forename: Ingrid
authors.initials: I
authors.lastname: Koziollek-Drechsler
authors.forename: Rebecca
authors.initials: R
authors.lastname: Wade
authors.forename: Christian
authors.initials: C
authors.lastname: Behl
authors.forename: Albrecht M
authors.initials: AM
authors.lastname: Clement
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000690:Amyotrophic Lateral Sclerosis / Q000201:enzymology* / Q000235:genetics*; D000818:Animals; D030801:Animals, Genetically Modified; D017173:Caenorhabditis elegans / Q000235:genetics / Q000502:physiology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D019281:Dimerization; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D051379:Mice; D009046:Motor Neurons / Q000201:enzymology / Q000502:physiology; D050050:Protein Carbonylation; D017434:Protein Structure, Tertiary; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D013482:Superoxide Dismutase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000072105:Superoxide Dismutase-1
chemical_list: D011993:Recombinant Fusion Proteins; C000606290:SOD1 protein, human; D006861:Hydrogen Peroxide; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1