Article abstract
Nature Cell Biology 2, 863 - 870 (2000)
Published online: 10 November 2000 | doi:10.1038/35046500
Upregulation of BiP and CHOP by the unfolded-protein response is independent of presenilin expression
Naoyuki Sato1, Fumihiko Urano2, Jae Yoon Leem1, Seong-Hun Kim1, Mingqing Li3, Dorit Donoviel4, Alan Bernstein4, Amy S. Lee3, David Ron2, Margaret L. Veselits1, Sangram S. Sisodia1 & Gopal Thinakaran1
Abstract
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 IRE1
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.
- Department of Neurobiology, Pharmacology and Physiology, The University of Chicago, Knapp R212, 924 East 57th street , Chicago, Illinois, 60637, USA
- Skirball Institute of Biomolecular Medicine, New York University Medical School, New York, New York 10016, USA
- Department of Biochemistry and Molecular Biology, USC/Norris Comprehensive Cancer Center, University of Southern California Keck School of Medicine, Los Angeles, California, 90089 , USA
- Samuel Lunenfeld Research Institute of Mount Sinai Hospital, Department of Molecular and Medical Genetics, University of Toronto , Toronto, Ontario, M5S-1A8, Canada .
Correspondence to: Gopal Thinakaran1 e-mail: gopal@uchicago.edu
