Presenilin-1 mutations downregulate the signalling pathway of the unfolded-protein response (original) (raw)

Nature Cell Biology volume 1, pages 479–485 (1999)Cite this article

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.

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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.

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Author notes

  1. Taiichi Katayama, Kazunori Imaizumi, Naoya Sato and Peter St George-Hyslop: These authors contributed equally to this work

Authors and Affiliations

  1. Department of Anatomy and Neuroscience, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan
    Taiichi Katayama, Kazunori Imaizumi, Naoya Sato, Ko Miyoshi, Junichi Hitomi, Takunari Yoneda, Fumi Gomi, Yasutake Mori & Masaya Tohyama
  2. Discovery Research Laboratory, Tanabe Seiyaku Co. Ltd, 3-16-89 Kashima, Yodogawaku, Osaka, 532-0031, Japan
    Taiichi Katayama, Kazunori Imaizumi & Naoya Sato
  3. CREST of Japan Science and Technology Corporation (JST), 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan
    Taiichi Katayama, Kazunori Imaizumi, Naoya Sato, Ko Miyoshi, Junichi Hitomi, Takashi Morihara, Takunari Yoneda, Fumi Gomi, Yasutake Mori & Masaya Tohyama
  4. Department of Clinical Neuroscience, Psychiatry, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan
    Takashi Kudo, Takashi Morihara, Yuka Nakano & Masatoshi Takeda
  5. Department of Social and Environmental Medicine, H3 Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan
    Junji Takeda
  6. Department of Neurology, Tohoku University School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai, 980-8574, Japan
    Takehide Tsuda & Yasuto Itoyama
  7. Laboratory for Alzheimer’s Disease, Brain Science Institute, RIKEN, 2-1 Hirosawa, Wako-shi, Saitama, 351-0198, Japan
    Ohoshi Murayama & Akihiko Takashima
  8. Department of Medicine (Neurology), Center for Research into Neurodegenerative Diseases, University of Toronto, Toronto, Ontario, M5S 1A8, Canada
    Peter St George-Hyslop

Authors

  1. Taiichi Katayama
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  2. Kazunori Imaizumi
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  3. Naoya Sato
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  4. Ko Miyoshi
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  5. Takashi Kudo
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  6. Junichi Hitomi
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  7. Takashi Morihara
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  8. Takunari Yoneda
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  9. Fumi Gomi
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  10. Yasutake Mori
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  11. Yuka Nakano
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  12. Junji Takeda
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  13. Takehide Tsuda
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  14. Yasuto Itoyama
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  15. Ohoshi Murayama
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  16. Akihiko Takashima
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  17. Peter St George-Hyslop
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  18. Masatoshi Takeda
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  19. Masaya Tohyama
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Corresponding author

Correspondence toKazunori Imaizumi.

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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

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