Subunit-Destabilizing Mutations in Drosophila Copper/Zinc Superoxide Dismutase: Neuropathology and a Model of Dimer Dysequilibrium

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 92; no. 19; pp. 8574 - 8578
• Main Authors: Phillips, John P., Tainer, John A., Getzoff, Elizabeth D., Boulianne, Gabrielle L., Kirby, Kim, Hilliker, Arthur J.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences of the United States of America 12-09-1995; National Acad Sciences; National Academy of Sciences
• Subjects: Alleles; Amino Acid Sequence; Amyotrophic Lateral Sclerosis - etiology; Animals; Base Sequence; Dimers; Drosophila; Drosophila melanogaster - enzymology; Drosophila melanogaster - genetics; Genetic mutation; Genetics; Heterozygote; Heterozygotes; Human genetics; Hydrogen bonds; Insects; Medical genetics; Medical research; Models, Chemical; Models, Molecular; Molecular Sequence Data; Mutation; Neurological disorders; Neurons; Photoreceptor Cells, Invertebrate - pathology; Photoreceptors; Protein Conformation; Retina - pathology; Sequence Analysis, DNA; Superoxide Dismutase - genetics
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.92.19.8574

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.