ALG-3, a truncated mouse homologue of the chromosome 1 familial Alzheimer's disease gene PS2, rescues T hybridoma 3DO cells from T-cell receptor-induced apoptosis by inhibiting Fas ligand induction and Fas signaling. Here we show that ALG-3 transfected 3DO cells express a COOH-terminal PS2 polypeptide. Overexpression of PS2 in ALG-3 transfected 3DO cells reconstitutes sensitivity to receptor-induced cell death, suggesting that the artificial PS2 polypeptide functions as a dominant negative mutant of PS2. ALG-3 and antisense PS2 protect PC12 cells from glutamate-induced apoptosis but not from death induced by hydrogen peroxide or the free radical MPP+. Thus, the PS2 gene is required for some forms of cell death in diverse cell types, and its function is opposed by ALG-3.