Fibroblasts from FAD-linked presenilin 1 mutations display a normal unfolded protein response but overproduce Abeta42 in response to tunicamycin.
Many patients affected by early onset familial Alzheimer's disease (FAD), carry mutations in the presenilin 1 (PS1) gene. Since it has been suggested that FAD-linked PS1 mutations impair the unfolded protein response (UPR) due to endoplasmic reticulum (ER) stress, we analyzed the UPR and amyloid beta-protein processing in fibroblasts bearing various PS1 mutations. Neither in normal conditions nor after induction of ER stress with DTT or tunicamycin were the mRNA levels of UPR-responsive genes (BiP and PDI) significantly different in control and FAD fibroblasts. DTT, which blocked APP transport to the Golgi, caused a 30% decrease of secreted Abeta42 in wild type and PS1 mutant fibroblasts. In contrast, tunicamycin, which allowed exit of APP from the ER, increased secreted Abeta42 only in PS1 mutant fibroblasts. Our findings suggest that, although the UPR is active in fibroblasts from FAD patients, mutant PS1 may selectively increase Abeta42 secretion when N-glycosylation is impaired.
Department of Neurosciences, Ophthalmology and Genetics, University of Genoa, 16132 Genoa, Italy.
Alessandra
A
Piccini
Anna
A
Fassio
Elena
E
Pasqualetto
Antonella
A
Vitali
Roberta
R
Borghi
Daniela
D
Palmieri
Benedetta
B
Nacmias
Sandro
S
Sorbi
Roberto
R
Sitia
Massimo
M
Tabaton
D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000096:biosynthesis* / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics; D002478:Cells, Cultured; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D000091342:Endoplasmic Reticulum Chaperone BiP; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism*; D006023:Glycoproteins / Q000235:genetics; D006031:Glycosylation / Q000187:drug effects; D006360:Heat-Shock Proteins; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics*; D018832:Molecular Chaperones / Q000235:genetics; D010446:Peptide Fragments / Q000096:biosynthesis* / Q000378:metabolism; D053764:Presenilin-1; D017510:Protein Folding; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D013312:Stress, Physiological / Q000378:metabolism / Q000503:physiopathology; D014415:Tunicamycin / Q000494:pharmacology*
D016229:Amyloid beta-Peptides; D002352:Carrier Proteins; D000091342:Endoplasmic Reticulum Chaperone BiP; D006023:Glycoproteins; D006360:Heat-Shock Proteins; D008565:Membrane Proteins; D018832:Molecular Chaperones; C508853:PSEN1 protein, human; D010446:Peptide Fragments; D053764:Presenilin-1; D012333:RNA, Messenger; C075222:amyloid beta-protein (1-42); D014415:Tunicamycin