NR AXAN
AU Jodoin,J.; Laroche-Pierre,S.; Goodyer,C.G.; LeBlanc,A.C.
TI Defective retrotranslocation causes loss of anti-Bax function in human familial prion protein mutants
QU Journal of Neuroscience 2007 May 9; 27(19): 5081-91
PT journal article; research support, n.i.h., extramural; research support, non-u.s. gov't
AB 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.
IN Das normale Prionprotein unterdrückt die Aktivierung der Bax-Gens, welches seinerseits den zellulären Selbstmord (Apoptose) fördert. Sämtliche von Jodoin et al. untersuchten zu CJK oder fataler familiärer Insomnie führenden Mutatioen des Prionproteins reduzierten diese Wirkung des Prionproteins. Anscheinend kommt es dazu aufgrund reduzierter Konzentrationen zytosolischen Prionproteins.
MH Animals; Apoptosis/*genetics; Cell Line, Tumor; Cell Membrane/metabolism; Cells, Cultured; Cytoplasm/metabolism; Glycosylphosphatidylinositols/metabolism; Humans; Mutation/*genetics; Prion Diseases/genetics/*metabolism; Prions/*genetics/*metabolism; Protein Folding; Protein Transport/genetics/physiology; Transfection; bcl-2-Associated X Protein/genetics/*metabolism
AD Bloomfield Center for Research in Aging, Lady Davis Institute for Medical Research, Sir Mortimer B. Davis Jewish General Hospital, Montreal, Quebec, Canada H3T 1E2.
SP englisch
PO USA