Mutations associated with amyotrophic lateral sclerosis convert superoxide dismutase from an antiapoptotic gene to a proapoptotic gene: Studies in yeast and neural cells

Shahrooz Rabizadeh, Edith Butler Gralla, David R. Borchelt, Ryder Gwinn, Joan Selverstone Valentine, Sangram Sisodia, Philip Wong, Michael Lee, Hejin Hahn, Dale E. Bredesen

Research output: Contribution to journalArticle

317 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)3024-3028
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume92
Issue number7
DOIs
StatePublished - Mar 28 1995

Keywords

  • SOD1 gene
  • Saccharomyces cerevisiae

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