title: Loss of anti-Bax function in Gerstmann-Sträussler-Scheinker syndrome-associated prion protein mutants.
abstract: 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.
authors.affiliation: Bloomfield Center for Research in Aging, Lady Davis Institute for Medical Research, Sir Mortimer B. Davis Jewish General Hospital, Montréal, Canada.
authors.forename: Julie
authors.initials: J
authors.lastname: Jodoin
authors.forename: Micheal
authors.initials: M
authors.lastname: Misiewicz
authors.forename: Priya
authors.initials: P
authors.lastname: Makhijani
authors.forename: Paresa N
authors.initials: PN
authors.lastname: Giannopoulos
authors.forename: Jennifer
authors.initials: J
authors.lastname: Hammond
authors.forename: Cynthia G
authors.initials: CG
authors.lastname: Goodyer
authors.forename: Andréa C
authors.initials: AC
authors.lastname: LeBlanc
mesh_terms: D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D053938:DNA Fragmentation; D004789:Enzyme Activation; D016098:Gerstmann-Straussler-Scheinker Disease / Q000235:genetics*; D006801:Humans; D009154:Mutation; D011328:Prions / Q000235:genetics*; D051028:bcl-2-Associated X Protein / Q000235:genetics*
chemical_list: D011328:Prions; D051028:bcl-2-Associated X Protein; D020169:Caspases
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