Upregulation of BiP and CHOP by the unfolded-protein response is independent of presenilin expression.
Presenilin 1 (PS1), a polytopic membrane protein, has a critical role in the trafficking and proteolysis of a selected set of transmembrane proteins. The vast majority of individuals affected with early onset familial Alzheimer's disease (FAD) carry missense mutations in PS1. Two studies have suggested that loss of PS1 function, or expression of FAD-linked PS1 variants, compromises the mammalian unfolded-protein response (UPR), and we sought to evaluate the potential role of PS1 in the mammalian UPR. Here we show that that neither the endoplasmic reticulum (ER) stress-induced accumulation of BiP and CHOP messenger RNA, nor the activation of ER stress kinases IRE1alpha and PERK, is compromised in cells lacking both PS1 and PS2 or in cells expressing FAD-linked PS1 variants. We also show that the levels of BiP are not significantly different in the brains of individuals with sporadic Alzheimer's disease or PS1-mediated FAD to levels in control brains. Our findings provide evidence that neither loss of PS1 and PS2 function, nor expression of PS1 variants, has a discernable impact on ER stress-mediated induction of the several established 'readouts' of the UPR pathway.
Sato
N
N
Department of Neurobiology, Pharmacology and Physiology, The University of Chicago, Knapp R212, 924 East 57th street, Chicago, Illinois, 60637, USA.
Urano
F
F
Yoon Leem
J
J
Kim
S H
SH
Li
M
M
Donoviel
D
D
Bernstein
A
A
Lee
A S
AS
Ron
D
D
Veselits
M L
ML
Sisodia
S S
SS
Thinakaran
G
G
D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism; D000818:Animals; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics*; D002352:Carrier Proteins / Q000235:genetics*; D002460:Cell Line; D004721:Endoplasmic Reticulum / Q000378:metabolism; D000091342:Endoplasmic Reticulum Chaperone BiP; D014644:Genetic Variation; D006360:Heat-Shock Proteins; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018832:Molecular Chaperones / Q000235:genetics*; D053764:Presenilin-1; D053766:Presenilin-2; D011489:Protein Denaturation; D017510:Protein Folding; D011506:Proteins / Q000737:chemistry / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051742:Transcription Factor CHOP; D014157:Transcription Factors / Q000235:genetics*; D015854:Up-Regulation
D022762:CCAAT-Enhancer-Binding Proteins; D002352:Carrier Proteins; C497249:DDIT3 protein, human; C497250:Ddit3 protein, mouse; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins; D008565:Membrane Proteins; D018832:Molecular Chaperones; C508853:PSEN1 protein, human; C508861:PSEN2 protein, human; D053764:Presenilin-1; D053766:Presenilin-2; D011506:Proteins; D012333:RNA, Messenger; D014157:Transcription Factors; D051742:Transcription Factor CHOP