title: Neurons overexpressing mutant presenilin-1 are more sensitive to apoptosis induced by endoplasmic reticulum-Golgi stress.
abstract: Most early-onset cases of familial Alzheimer's disease (FAD) are linked to mutations in two related genes, ps1 and ps2. FAD-linked mutant PS1 alters proteolytic processing of the amyloid precursor protein and increases vulnerability to apoptosis induced by various cell stresses. In transfected cell lines, mutations in ps1 decrease the unfolded-protein response (UPR), which is the response to the increased amounts of unfolded proteins that accumulate in the endoplamic reticulum (ER), indicating that these mutations may increase vulnerability to ER stress by altering the UPR signalling pathway. Here we report that, in primary cultured neurons from cortices of transgenic mice, overexpression of mutated PS1 (M146L mutation) but not PS1 wild-type (wt) enhanced spontaneous neuronal apoptosis that involved oxidative stress and caspase activation. In PS1M146L cultures, neurons displaying immunoreactivity for human PS1 were threefold more vulnerable to spontaneous apoptosis than the overall neuronal population. In addition, PS1M146L transgenic neurons were more sensitive to apoptosis induced by various stresses, including two ER-Golgi toxins, nordihydroguaiatric acid and brefeldin A (also known to induce UPR), as well as staurosporine. In contrast, PS1 wt transgenic neurons were resistant to apoptosis induced by Golgi-ER toxins but displayed a comparable vulnerability to staurosporine. Our study demonstrates that, as previously reported, overexpression of FAD-linked mutant PS1 enhances neuronal vulnerability to spontaneous and induced apoptosis. In addition, we show that this vulnerability was correlated with mutant PS1 protein expression and that PS1 wt overexpression selectively prevented ER-Golgi stress-induced apoptosis. These data indicate that PS1 interferes with a specific apoptotic pathway that results from a dysfunction of the ER-Golgi compartment.
authors.affiliation: Department of Histology and Cell Biology, Faculty of Medicine, Limoges, France. faraj.terro@unilim.fr
authors.forename: Faraj
authors.initials: F
authors.lastname: Terro
authors.forename: Christian
authors.initials: C
authors.lastname: Czech
authors.forename: Françoise
authors.initials: F
authors.lastname: Esclaire
authors.forename: Wassim
authors.initials: W
authors.lastname: Elyaman
authors.forename: Catherine
authors.initials: C
authors.lastname: Yardin
authors.forename: Marie-Claire
authors.initials: MC
authors.lastname: Baclet
authors.forename: Nathalie
authors.initials: N
authors.lastname: Touchet
authors.forename: Günter
authors.initials: G
authors.lastname: Tremp
authors.forename: Laurent
authors.initials: L
authors.lastname: Pradier
authors.forename: Jacques
authors.initials: J
authors.lastname: Hugon
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics*; D020126:Brefeldin A / Q000494:pharmacology; D020169:Caspases / Q000378:metabolism; D002478:Cells, Cultured; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005333:Fetus; D006056:Golgi Apparatus / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D009637:Masoprocol / Q000494:pharmacology; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000187:drug effects / Q000235:genetics*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects / Q000235:genetics*; D053764:Presenilin-1; D017510:Protein Folding; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D019311:Staurosporine / Q000494:pharmacology
chemical_list: D016564:Amyloid beta-Protein Precursor; D016861:Cyclooxygenase Inhibitors; D004791:Enzyme Inhibitors; D008565:Membrane Proteins; C508853:PSEN1 protein, human; D053764:Presenilin-1; D011500:Protein Synthesis Inhibitors; D020126:Brefeldin A; D009637:Masoprocol; D020169:Caspases; D019311:Staurosporine