MUTATIONS ASSOCIATED WITH AMYOTROPHIC-LATERAL-SCLEROSIS CONVERT SUPEROXIDE-DISMUTASE FROM AN ANTIAPOPTOTIC GENE TO A PROAPOPTOTIC GENE - STUDIES IN YEAST AND NEURAL CELLS

Familial amyotrophic lateral sclerosis (FALS) is associated with mutat ions in SOD1, the gene encoding copper/zinc superoxide dismutase (CuZn SOD), However, the mechanism by which these mutations lead to amyotrop hic lateral sclerosis is unknown. We report that FALS mutant SODs expr essed in yeast lacking CuZnSOD are enzymatically active and restore th e yeast to the wild-type phenotype. In mammalian neural cells, the ove rexpression of wild-type SOD1 inhibits apoptosis induced by serum and growth factor withdrawal or calcium ionophore. In contrast, FALS-assoc iated SOD1 mutants promote, rather than inhibit, neural apoptosis, in a dominant fashion, despite the fact that these mutants retain enzymat ic SOD activity both in yeast and in mammalian neural cells. The resul ts dissociate the SOD activity of FALS-associated mutants from the ind uction of neural cell death, suggesting that FALS associated with muta tions in SOD1 may not be simply the result of a decrease in the enzyma tic function of CuZnSOD. Furthermore, the results provide an in vitro model that may help to define the mechanism by which FALS-associated S OD1 mutations lead to neural cell death.