SUBUNIT-DESTABILIZING MUTATIONS IN DROSOPHILA COPPER-ZINC SUPEROXIDE-DISMUTASE - NEUROPATHOLOGY AND A MODEL OF DIMER DYSEQUILIBRIUM

Mutations in Cu/Zn superoxide dismutase (SOD), a hallmark of familial amyotrophic lateral sclerosis (FALS) in humans, are shown here to conf er striking neuropathology in Drosophila, Heterozygotes with one wild- type and one deleted SOD allele retain the expected 50% of normal acti vity for this dimeric enzyme. However, heterozygotes with one, wild ty pe and one missense SOD allele show lesser SOD activities, ranging fro m 37% for a heterozygote carrying a missense mutation predicted from s tructural models to destabilize the dimer interface, to an average of 13% for several heterozygotes carrying missense mutations predicted to destabilize the subunit fold, Genetic and biochemical evidence sugges ts a model of dimer dysequilibrium whereby SOD activity in missense he terozygotes is reduced through entrapment of wild-type subunits into u nstable or enzymatically inactive heterodimers, This dramatic impairme nt of the activity of wild-type subunits in vivo has implications for our understanding of FALS and for possible therapeutic strategies.