Disease-associated mutations in SOD1 are impervious to dominant positive or negative effects

The familial form of amyotrophic lateral sclerosis is caused by mutations i n the SOD1 gene encoding the cytosolic antioxidant enzyme Cu,Zn superoxide dismutase. Although there is no clear correlation between disease and dismu tating catalytic activity among the various disease-associated SOD1 alleles , all of the known missense mutations significantly alter the half-life of the encoded polypeptides. Using transient transfection studies in mammalian cells, it was demonstrated that a frameshift mutation in SOD1 which result s in a truncated polypeptide is similarly destabilized. Using an epitope-ta gging strategy 60 discriminate between mutant and wild-type SOD1 polypeptid es, no evidence for dominant effects on polypeptide stability was detected, including that of a positive effect of the wild-type on mutant SOD1 polype ptides or that of a negative effect of mutant on wild-type SOD1 polypeptide s. These experiments thus favor a non-catalytic role of mutant forms of SOD 1 in disease progression. (C) 2000 Academic Press.