Abstract
Missense mutations in the human presenilin-1 (PS1) gene, which is found on chromosome 14, cause early-onset familial Alzheimer’s disease (FAD). FAD-linked PS1 variants alter proteolytic processing of the amyloid precursor protein and cause an increase in vulnerability to apoptosis induced by various cell stresses. However, the mechanisms responsible for these phenomena are not clear. Here we report that mutations in PS1 affect the unfolded-protein response (UPR), which responds to the increased amount of unfolded proteins that accumulate in the endoplasmic reticulum (ER) under conditions that cause ER stress. PS1 mutations also lead to decreased expression of GRP78/Bip, a molecular chaperone, present in the ER, that can enable protein folding. Interestingly, GRP78 levels are reduced in the brains of Alzheimer’s disease patients. The downregulation of UPR signalling by PS1 mutations is caused by disturbed function of IRE1, which is the proximal sensor of conditions in the ER lumen. Overexpression of GRP78 in neuroblastoma cells bearing PS1 mutants almost completely restores resistance to ER stress to the level of cells expressing wild-type PS1. These results show that mutations in PS1 may increase vulnerability to ER stress by altering the UPR signalling pathway.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Chartier-Harlin, M. C. et al. Early-onset Alzheimer’s disease caused by mutations at codon precursor protein gene. Nature 353, 844–846 (1991).
Goate, A. et al. Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer’s disease. Nature 349, 704–706 (1991).
Mullan, M. et al. A pathogenic mutation for probable Alzheimer’s disease in the APP gene at the N-terminus of beta-amyloid. Nature Genet. 1, 345–347 (1992).
Sherrington, R. et al. Cloning of a gene bearing missense mutations in early-onset familial Alzheimer’s disease. Nature 375, 754–760 (1995).
Levy-Lahad, E. et al. A familial Alzheimer’s disease locus on chromosome I. Science 269, 970–973 (1995).
Levy-Lahad, E. et al. Candidate gene for the chromosome 1 familial Alzheimer’s disease locus. Science 269, 973–977 (1995).
Rogaev, E. I. et al. Familial Alzheimer’s disease in kindreds with missense mutations in a gene on chromosome 1 related to the Alzheimer’s disease type 3 gene. Nature 376, 775–778 (1995).
Borchelt, D. R. et al. Familial Alzheimer’s disease-linked presenilin 1 variants elevate Aβ1-42/1-40 ratio in vitro and in vivo. Neuron 17, 1005–1013 (1996).
Duff, K. et al. Increased amyloid-β42(43) in brains of mice expressing mutant presenilin 1. Nature 383, 710–713 (1996).
Guo, Q. et al. Alzheimer’s presenilin mutation sensitizes neural cells to apoptosis induced by trophic factor withdrawal and amyloid β-peptide: involvement of calcium and oxyradicals. J. Neurosci. 17, 4212–4222 (1997).
Guo, Q. et al. Increased vulnerability of hippocampal neurons to excitotoxic necrosis in presenilin-1 mutant knock-in mice. Nature Med. 5, 101–106 (1999).
Kovacs, D. et al. Alzheimer-associated presenilin 1 and 2: neuronal expression in brain and localization to intracellular membranes in mammalian cells. Nature Med. 2, 224–229 (1996).
Sidrauski, C., Chapman, R. & Walter, P. The unfolded protein response: an intracellular signalling pathway with many surprising features. Trends Cell Biol. 8, 245–249 (1998).
Tirasophon, W., Welihinda, A. A. & Kaufman, R. J. A stress response pathway from the endoplasmic reticulum to the nucleus requires a novel bifunctional protein kinase/endoribonuclease (Ire1p) in mammalian cells. Genes Dev. 12, 1812–1824 (1998).
Wang, X.-Z. et al. Cloning of mammalian Ire1 reveals diversity in the ER stress responses. EMBO J. 17, 5708–5717 (1998).
Nakano, Y. et al. Accumulation of murine amyloid beta42 with a gene-dosage dependent manner in PS1 ‘knock-in’ mice. Eur. J. Neurosci. 11, 2577–2581 (1999).
Mori, K. et al. A 22 bp cis-acting element is necessary and sufficient for the induction of the yeast KAR2 (Bip) gene by unfolded protein. EMBO J. 11, 2583–2593 (1992).
Li, W. W., Sistonen, L., Morimoto, R. I. & Lee, A. S. Stress induction of the mammalian GRP78/BiP protein gene: in vivo genomic footprinting and identification of p70CORE from human nuclear extract as a DNA-binding component specific to the stress regulatory element. Mol. Cell. Biol. 14, 5533–5546 (1994).
Cox, J. S. & Walter, P. A novel mechanism for regulating activity of a transcription factor that controls the unfolded protein response. Cell 87, 391–404 (1996).
Zhang, J. et al. Subcellular distribution and turnover of presenilins in transfected cells. J. Biol. Chem. 273, 12436–12442 (1998).
Gomer, C. et al. Glucose regulated protein induction and cellular resistance to oxidative stress mediated by porphyrin photosensitization. Cancer Res. 51, 6574–6579 (1991).
Li, L. J. et al. Establishment of a Chinese hamster ovary cell line that expresses grp78 antisense transcripts and suppresses A23187 induction of both GRP78 and GRP94. J.Cell Physiol. 153, 575–582 (1992).
Sugawara, S., Takeda, K., Lee, A. & Dennert, G. Suppression of stress protein GRP78 induction in tumor B/C10ME eliminates resistance to cell mediated cytotoxicity. Cancer Res. 53, 6001–6005 (1993).
Shamu, C. E. & Walter, P. Oligomerization and phosphorylation of the Ire1p kinase during intracellular signaling from the endoplasmic reticulum to the nucleus. EMBO J. 15, 3028–3039 (1996).
Welihinda, A. A., Tirasophon, W., Green, S. & Kaufman, R. J. Protein serine/threonine phosphatase Ptc2p negatively regulates the unfolded-protein response by dephosphorylating Ire1p kinase. Mol. Cell. Biol. 18, 1967–1977 (1998).
Cook, D. G. et al. Alzheimer’s Aβ(1-42) is generated in the endoplasmic reticulum/intermediate compartment of NT2N cells. Nature Med. 3, 1021–1023 (1997).
Hammond, C. & Helenius, A. Quality control in the secretory pathway: retention of a misfolded viral membrane glycoprotein involves cycling between the ER, intermediate compartment, and Golgi apparatus. J. Cell. Biol. 126, 41–52 (1994).
Yang, Y., Turner, R. S. & Gaut, J. R. The chaperone Bip/GRP78 binds to amyloid precursor protein and decrease Aβ40 and Aβ42 secretion. J. Biol. Chem. 273, 25552–25555 (1998).
Murayama, O. et al. Enhancement of amyloid β42 secretion by 28 different presenilin 1 mutations of familial Alzheimer’s disease. Neurosci. Lett. 265, 61–63 (1999).
Shapiro, D. J., Sharp, P. A., Wahli, W. W. & Keller, M. J. A high-efficiency HeLa cell nuclear transcription extract. DNA 7, 47–55 (1988).
Bruce, A. J., Malfroy, B. & Baudry, M. β-Amyloid toxicity in organotypic cultures: protection by EUK-8, a synthetic catalytic free radical scavenger. Proc. Natl Acad. Sci. USA 93, 2312–2316 (1996).
Acknowledgements
We thank K. Iqbal for the Tau expression vector and anti-Tau antibody; and T. Iwasaki for helpful discussions and critical reading of this manuscript.
Correspondence and requests for materials should be addressed to K.I.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Katayama, T., Imaizumi, K., Sato, N. et al. Presenilin-1 mutations downregulate the signalling pathway of the unfolded-protein response. Nat Cell Biol 1, 479–485 (1999). https://doi.org/10.1038/70265
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/70265
This article is cited by
-
Susceptibility to cellular stress in PS1 mutant N2a cells is associated with mitochondrial defects and altered calcium homeostasis
Scientific Reports (2020)
-
Molecular Mechanisms of ER Stress and UPR in the Pathogenesis of Alzheimer’s Disease
Molecular Neurobiology (2020)
-
A New Endoplasmic Reticulum (ER)-Targeting Fluorescent Probe for the Imaging of Cysteine in Living Cells
Journal of Fluorescence (2020)
-
Molecular mechanisms driving transcriptional stress responses
Nature Reviews Genetics (2018)
-
Endoplasmic reticulum stress and inflammation in the central nervous system
Molecular Neurodegeneration (2017)
