title: Defective retrotranslocation causes loss of anti-Bax function in human familial prion protein mutants.
abstract: 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.
authors.affiliation: Bloomfield Center for Research in Aging, Lady Davis Institute for Medical Research, Sir Mortimer B. Davis Jewish General Hospital, Montréal, Québec, Canada H3T 1E2.
authors.forename: Julie
authors.initials: J
authors.lastname: Jodoin
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Laroche-Pierre
authors.forename: Cynthia G
authors.initials: CG
authors.lastname: Goodyer
authors.forename: Andréa C
authors.initials: AC
authors.lastname: LeBlanc
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D003593:Cytoplasm / Q000378:metabolism; D017261:Glycosylphosphatidylinositols / Q000378:metabolism; D006801:Humans; D009154:Mutation / Q000235:genetics*; D017096:Prion Diseases / Q000235:genetics / Q000378:metabolism*; D011328:Prions / Q000235:genetics* / Q000378:metabolism*; D017510:Protein Folding; D021381:Protein Transport / Q000235:genetics / Q000502:physiology; D014162:Transfection; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D017261:Glycosylphosphatidylinositols; D011328:Prions; D051028:bcl-2-Associated X Protein