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 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.
Phillips
J P
JP
Department of Molecular Biology and Genetics, University of Guelph, ON Canada.
Tainer
J A
JA
Getzoff
E D
ED
Boulianne
G L
GL
Kirby
K
K
Hilliker
A J
AJ
D000595:Amino Acid Sequence; D000690:Amyotrophic Lateral Sclerosis / Q000209:etiology*; D000818:Animals; D001483:Base Sequence; D004331:Drosophila melanogaster / Q000201:enzymology / Q000235:genetics*; D006579:Heterozygote; D008956:Models, Chemical; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D017956:Photoreceptor Cells, Invertebrate / Q000473:pathology*; D011487:Protein Conformation; D012160:Retina / Q000473:pathology*; D017422:Sequence Analysis, DNA; D013482:Superoxide Dismutase / Q000235:genetics*
D013482:Superoxide Dismutase