DOI: 10.1083/jcb.200104045. The discrepancy between presenilin subcellular localization and <b>γ</b>-secretase processing of amyloid precursor protein

The discrepancy between presenilin subcellular localization and γ-secretase processing of amyloid precursor protein

10.1083/jcb.200104045

Crossref journal-article

Rockefeller University Press

The Journal of Cell Biology (291)

Abstract

We investigated the relationship between PS1 and γ-secretase processing of amyloid precursor protein (APP) in primary cultures of neurons. Increasing the amount of APP at the cell surface or towards endosomes did not significantly affect PS1-dependent γ-secretase cleavage, although little PS1 is present in those subcellular compartments. In contrast, almost no γ-secretase processing was observed when holo-APP or APP-C99, a direct substrate for γ-secretase, were specifically retained in the endoplasmic reticulum (ER) by a double lysine retention motif. Nevertheless, APP-C99-dilysine (KK) colocalized with PS1 in the ER. In contrast, APP-C99 did not colocalize with PS1, but was efficiently processed by PS1-dependent γ-secretase. APP-C99 resides in a compartment that is negative for ER, intermediate compartment, and Golgi marker proteins. We conclude that γ-secretase cleavage of APP-C99 occurs in a specialized subcellular compartment where little or no PS1 is detected. This suggests that at least one other factor than PS1, located downstream of the ER, is required for the γ-cleavage of APP-C99. In agreement, we found that intracellular γ-secretase processing of APP-C99-KK both at the γ40 and the γ42 site could be restored partially after brefeldin A treatment. Our data confirm the “spatial paradox” and raise several questions regarding the PS1 is γ-secretase hypothesis.

Bibliography

Cupers, P., Bentahir, M., Craessaerts, K., Orlans, I., Vanderstichele, H., Saftig, P., De Strooper, B., & Annaert, W. (2001). The discrepancy between presenilin subcellular localization and Î³-secretase processing of amyloid precursor protein. The Journal of Cell Biology, 154(4), 731â740.

Authors 8

Philippe Cupers (first)
Mustapha Bentahir (additional)
Katleen Craessaerts (additional)
Isabelle Orlans (additional)
Hugo Vanderstichele (additional)
Paul Saftig (additional)
Bart De Strooper (additional)
Wim Annaert (additional)

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Dates

Type	When
Created	23 years, 1 month ago (July 26, 2002, 12:46 p.m.)
Deposited	2 years ago (July 29, 2023, 12:30 a.m.)
Indexed	1 month, 1 week ago (July 14, 2025, 11:17 p.m.)
Issued	24 years ago (Aug. 13, 2001)
Published	24 years ago (Aug. 13, 2001)
Published Online	24 years ago (Aug. 13, 2001)
Published Print	24 years ago (Aug. 20, 2001)

Funders 0

None

BibTeX

@article{Cupers_2001, title={The discrepancy between presenilin subcellular localization and γ-secretase processing of amyloid precursor protein}, volume={154}, ISSN={0021-9525}, url={http://dx.doi.org/10.1083/jcb.200104045}, DOI={10.1083/jcb.200104045}, number={4}, journal={The Journal of Cell Biology}, publisher={Rockefeller University Press}, author={Cupers, Philippe and Bentahir, Mustapha and Craessaerts, Katleen and Orlans, Isabelle and Vanderstichele, Hugo and Saftig, Paul and De Strooper, Bart and Annaert, Wim}, year={2001}, month=aug, pages={731–740} }

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  "abstract": "<jats:p>We investigated the relationship between PS1 and \u03b3-secretase processing of amyloid precursor protein (APP) in primary cultures of neurons. Increasing the amount of APP at the cell surface or towards endosomes did not significantly affect PS1-dependent \u03b3-secretase cleavage, although little PS1 is present in those subcellular compartments. In contrast, almost no \u03b3-secretase processing was observed when holo-APP or APP-C99, a direct substrate for \u03b3-secretase, were specifically retained in the endoplasmic reticulum (ER) by a double lysine retention motif. Nevertheless, APP-C99-dilysine (KK) colocalized with PS1 in the ER. In contrast, APP-C99 did not colocalize with PS1, but was efficiently processed by PS1-dependent \u03b3-secretase. APP-C99 resides in a compartment that is negative for ER, intermediate compartment, and Golgi marker proteins. We conclude that \u03b3-secretase cleavage of APP-C99 occurs in a specialized subcellular compartment where little or no PS1 is detected. This suggests that at least one other factor than PS1, located downstream of the ER, is required for the \u03b3-cleavage of APP-C99. In agreement, we found that intracellular \u03b3-secretase processing of APP-C99-KK both at the \u03b340 and the \u03b342 site could be restored partially after brefeldin A treatment. Our data confirm the \u201cspatial paradox\u201d and raise several questions regarding the PS1 is \u03b3-secretase hypothesis.</jats:p>",
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