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Presenilin-1 Holoprotein is an Interacting Partner of Sarco Endoplasmic Reticulum Calcium-ATPase and Confers Resistance to Endoplasmic Reticulum Stress

Article type: Research Article

Authors: Jin, Haifenga | Sanjo, Nobuoa; * | Uchihara, Toshikib | Watabe, Kazuhikoc | George-Hyslop, Peter St.d; e | Fraser, Paul E.d | Mizusawa, Hidehiroa

Affiliations: [a] Department of Neurology and Neurological Science, Graduate School of Medical and Dental Science, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, Japan | [b] Department of Neurology, Tokyo Metropolitan Institute for Neuroscience, Fuchu, Tokyo, Japan | [c] Molecular Neuropathology, Tokyo Metropolitan Institute for Neuroscience, Fuchu, Tokyo, Japan | [d] Centre for Research in Neurodegenerative Diseases, Departments of Medical Biophysics and Medicine (Neurology), University of Toronto, Toronto, Ontario, Canada | [e] Department of Clinical Neuroscience, University of Cambridge, Cambridge, United Kingdom

Correspondence: [*] Correspondence to: Nobuo Sanjo, Department of Neurology and Neurological Science, Graduate School of Medical and Dental Science, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519 Japan. Tel.: +81 3 5803 5234; Fax: +81 3 5803 0169; E-mail: n-sanjo.nuro@tmd.ac.jp.

Keywords: Endoplasmic reticulum stress, presenilin, PS1, PSEN1, PS2, PSEN2, sarco ER calcium-ATPase, SERCA, tunicamycin

DOI: 10.3233/JAD-2010-1360

Journal: Journal of Alzheimer's Disease, vol. 20, no. 1, pp. 261-273, 2010

Accepted 15 December 2009
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Published: 24 March 2010
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Supplementary Materials:

Supplementary Materials.

Abstract

Presenilin-1 (PSEN1) is a primary component of the γ-secretase complex, and total levels of its holoprotein and endoproteolytic fragments are tightly regulated. We examined the effects of several types of endoplasmic reticulum (ER) stress on quantitative changes in the levels of PSEN1 mRNA, holoprotein, and fragments. The ER stress-inducing chemical compounds tunicamycin, brefeldin-A, thapsigargin, and staurosporine were added to the culture media of various human cell lines. Tunicamycin treatment caused a doubling of PSEN1 holoprotein production in HEK293 cells and an increase in holoprotein production to approximately 180% in GOTO human neuroblastoma and KNS-42 human glioma cell lines, without changing the amounts of PSEN1 N- or C-terminal fragments. The elevated holoprotein level in HEK293 cells was accompanied by an increase in PSEN1 mRNA expression. HEK293 cells that stably overexpressed PSEN1 holoprotein showed increased resistance to ER stress induced by tunicamycin, but they did not show resistance to ER stress caused by thapsigargin, a specific inhibitor of sarco ER calcium-ATPase (SERCA). In wild-type HEK293 cells under ER stress induced by tunicamycin, an increased amount of SERCA interacted with PSEN1 holoprotein. PSEN1 production varied among cell types and circumstances. The results suggested that the holoprotein forms a complex with the SERCA channel and participates in the regulation of intracellular calcium homeostasis. These findings provide support for the calcium hypothesis of Alzheimer's disease.

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