Phillips, J.P., Tainer, J.A., Getzoff, E.D., Boulianne, G.L., Kirby, K., Hilliker, A.J. (1995). Subunit-destabilizing mutations in Drosophila copper zinc superoxide dismutase: Neuropathology and a model of dimer dysequilibrium.  Proc. Natl. Acad. Sci. U.S.A. 92(19): 8574--8578.

FBrf0084265

Research paper

Mutations in Cu/Zn superoxide dismutase (SOD), a hallmark of familial amyotrophic lateral sclerosis (FALS) in humans, are shown here to confer striking neuropathology in Drosophila. Heterozygotes with one wild-type and one deleted SOD allele retain the expected 50% of normal activity for this dimeric enzyme. However, heterozygotes with one wild-type and one missense SOD allele show lesser SOD activities, ranging from 37% for a heterozygote carrying a missense mutation predicted from structural 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 suggests a model of dimer dysequilibrium whereby SOD activity in missense heterozygotes is reduced through entrapment of wild-type subunits into unstable or enzymatically inactive heterodimers. This dramatic impairment of the activity of wild-type subunits in vivo has implications for our understanding of FALS and for possible therapeutic strategies.

PMC41008 (PMC) (EuropePMC)