Previously, we have shown the loss of anti-Bax function in Creutzfeldt Jakob 
disease (CJD)-associated prion protein (PrP) mutants that are unable to generate 
cytosolic PrP (CyPrP). To determine if the anti-Bax function of PrP modulates 
the manifestation of prion diseases, we further investigated the anti-Bax 
function of eight familial Gerstmann-Sträussler-Scheinker Syndrome 
(GSS)-associated PrP mutants. These PrP mutants contained their respective 
methionine ((M)) or valine ((V)) at codon 129. All of the mutants lost their 
ability to prevent Bax-mediated chromatin condensation or DNA fragmentation in 
primary human neurons. In the breast carcinoma MCF-7 cells, the F198S(V), 
D202N(V), P102L(V) and Q217R(V) retained, whereas the P102L(M), P105L(V), 
Y145stop(M) and Q212P(M) PrP mutants lost their ability to inhibit Bax-mediated 
condensed chromatin. The inhibition of Bax-mediated condensed chromatin depended 
on the ability of the mutants to generate cytosolic PrP. However, except for the 
P102L(V), none of the mutants significantly inhibited Bax-mediated caspase 
activation. These results show that the cytosolic PrP generated from the GSS 
mutants is not as efficient as wild type PrP in inhibiting Bax-mediated cell 
death. Furthermore, these results indicate that the anti-Bax function is also 
disrupted in GSS-associated PrP mutants and is not associated with the 
difference between CJD and GSS.