Prion protein (PrP) inhibits the activation of proapoptotic Bax in primary human 
neurons and MCF-7 cells. Because neuronal apoptosis occurs in human prion 
diseases, here we examine the anti-Bax function of familial PrP mutants. All 
Creutzfeldt-Jakob disease and fatal familial insomnia-associated prion protein 
mutations partially or completely lose the anti-Bax function in human neurons 
and, except for A117V and V203I, in MCF-7 cells. The ability of the mutants to 
protect against Bax-mediated cell death is divided into three groups: (1) group 
I, retention of anti-Bax function in both the Val129 and Met129 mutants; (2) 
group II, retention of anti-Bax function only in Val129 mutants; and (3) group 
III, reduction or no anti-Bax function in Val129 and Met129 mutants. The loss of 
anti-Bax function in these PrP mutants correlates completely with a significant 
decrease in the production of cytosolic PrP, a form of PrP shown previously to 
have anti-Bax function in human neurons. Cotransfection of the full-length PrP 
mutants with wild-type or mutant cytosolic PrP, but not with wild type 
full-length PrP, rescues the anti-Bax function of PrP. The results show that the 
failure of PrP mutants to produce cytosolic PrP is responsible for the loss of 
anti-Bax function and that the effect of the PrP mutants is dominant over 
wild-type PrP. Furthermore, these results imply that misfolded PrP that escapes 
retrotranslocation could accumulate at the cell surface and cause neuronal 
dysfunction.