title: Mutations associated with amyotrophic lateral sclerosis convert superoxide dismutase from an antiapoptotic gene to a proapoptotic gene: studies in yeast and neural cells.
abstract: Familial amyotrophic lateral sclerosis (FALS) is associated with mutations in SOD1, the gene encoding copper/zinc superoxide dismutase (CuZnSOD). However, the mechanism by which these mutations lead to amyotrophic lateral sclerosis is unknown. We report that FALS mutant SODs expressed in yeast lacking CuZnSOD are enzymatically active and restore the yeast to the wild-type phenotype. In mammalian neural cells, the overexpression of wild-type SOD1 inhibits apoptosis induced by serum and growth factor withdrawal or calcium ionophore. In contrast, FALS-associated SOD1 mutants promote, rather than inhibit, neural apoptosis, in a dominant fashion, despite the fact that these mutants retain enzymatic SOD activity both in yeast and in mammalian neural cells. The results dissociate the SOD activity of FALS-associated mutants from the induction of neural cell death, suggesting that FALS associated with mutations in SOD1 may not be simply the result of a decrease in the enzymatic function of CuZnSOD. Furthermore, the results provide an in vitro model that may help to define the mechanism by which FALS-associated SOD1 mutations lead to neural cell death.
authors.affiliation: Department of Neurology, University of California School of Medicine, Los Angeles 90024-1769, USA.
authors.forename: S
authors.initials: S
authors.lastname: Rabizadeh
authors.forename: E B
authors.initials: EB
authors.lastname: Gralla
authors.forename: D R
authors.initials: DR
authors.lastname: Borchelt
authors.forename: R
authors.initials: R
authors.lastname: Gwinn
authors.forename: J S
authors.initials: JS
authors.lastname: Valentine
authors.forename: S
authors.initials: S
authors.lastname: Sisodia
authors.forename: P
authors.initials: P
authors.lastname: Wong
authors.forename: M
authors.initials: M
authors.lastname: Lee
authors.forename: H
authors.initials: H
authors.lastname: Hahn
authors.forename: D E
authors.initials: DE
authors.lastname: Bredesen
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000201:enzymology* / Q000235:genetics*; D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D002461:Cell Line, Transformed; D003001:Cloning, Molecular; D017353:Gene Deletion; D015870:Gene Expression; D006801:Humans; D007527:Isoenzymes / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D007700:Kinetics; D009474:Neurons / Q000502:physiology*; D010269:Paraquat / Q000494:pharmacology; D017354:Point Mutation; D051381:Rats; D011994:Recombinant Proteins / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000235:genetics / Q000254:growth & development*; D013378:Substantia Nigra / Q000502:physiology*; D013482:Superoxide Dismutase / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D014162:Transfection
chemical_list: D007527:Isoenzymes; D011994:Recombinant Proteins; D013482:Superoxide Dismutase; D010269:Paraquat