Composition of soluble misfolded superoxide dismutase-1 in murine models of amyotrophic lateral sclerosis.

A common cause of amyotrophic lateral sclerosis is mutations in superoxide dismutase-1, which provoke the disease by an unknown mechanism. We have previously found that soluble hydrophobic misfolded mutant human superoxide dismutase-1 species are enriched in the vulnerable spinal cords of transgenic model mice. The levels were broadly inversely correlated with life spans, suggesting involvement in the pathogenesis. Here, we used methods based on antihuman superoxide dismutase-1 peptide antibodies specific for misfolded species to explore the composition and amounts of soluble misfolded human superoxide dismutase-1 in tissue extracts. Mice expressing 5 different human superoxide dismutase-1 variants with widely variable structural characteristics were examined. The levels were generally higher in spinal cords than in other tissues. The major portion of misfolded superoxide dismutase-1 was shown to be monomers lacking the C57-C146 disulfide bond with large hydrodynamic volume, indicating a severely disordered structure. The remainder of the misfolded protein appeared to be non-covalently associated in 130- and 250-kDa complexes. The malleable monomers should be prone to aggregate and associate with other cellular components, and should be easily translocated between compartments. They may be the primary cause of toxicity in superoxide dismutase-1-induced amyotrophic lateral sclerosis.