TY - JOUR T1 - Defective Retrotranslocation Causes Loss of Anti-Bax Function in Human Familial Prion Protein Mutants JF - The Journal of Neuroscience JO - J. Neurosci. SP - 5081 LP - 5091 DO - 10.1523/JNEUROSCI.0957-07.2007 VL - 27 IS - 19 AU - Julie Jodoin AU - Stéphanie Laroche-Pierre AU - Cynthia G. Goodyer AU - Andréa C. LeBlanc Y1 - 2007/05/09 UR - http://www.jneurosci.org/content/27/19/5081.abstract N2 - 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. ER -