A Role for Presenilin 1 in Regulating the Delivery of Amyloid Precursor Protein to the Cell Surface

Jae Yoon Leem; Carlos A. Saura; Claus Pietrzik; John Christianson; Christian Wanamaker; LaShaunda T. King; Margaret L. Veselits; Taisuke Tomita; Laura Gasparini; Takeshi Iwatsubo; Huaxi Xu; William N. Green; Edward H. Koo; Gopal Thinakaran

Neurobiology of Disease (Oct 2002)

A Role for Presenilin 1 in Regulating the Delivery of Amyloid Precursor Protein to the Cell Surface

Jae Yoon Leem,
Carlos A. Saura,
Claus Pietrzik,
John Christianson,
Christian Wanamaker,
LaShaunda T. King,
Margaret L. Veselits,
Taisuke Tomita,
Laura Gasparini,
Takeshi Iwatsubo,
Huaxi Xu,
William N. Green,
Edward H. Koo,
Gopal Thinakaran

Affiliations

Jae Yoon Leem: Department of Neurobiology, Pharmacology, and Physiology, University of Chicago, Chicago, Illinois, 60637; Committee on Neurobiology, University of Chicago, Chicago, Illinois, 60637; Department of Neurosciences, University of California at San Diego, La Jolla, California, 92093; Department of Neuropathology and Neuroscience, University of Tokyo, Tokyo, Japan; Laboratory of Molecular and Cellular Neuroscience, Rockefeller University, New York, New York, 10021
Carlos A. Saura: Department of Neurobiology, Pharmacology, and Physiology, University of Chicago, Chicago, Illinois, 60637; Committee on Neurobiology, University of Chicago, Chicago, Illinois, 60637; Department of Neurosciences, University of California at San Diego, La Jolla, California, 92093; Department of Neuropathology and Neuroscience, University of Tokyo, Tokyo, Japan; Laboratory of Molecular and Cellular Neuroscience, Rockefeller University, New York, New York, 10021
Claus Pietrzik: Department of Neurobiology, Pharmacology, and Physiology, University of Chicago, Chicago, Illinois, 60637; Committee on Neurobiology, University of Chicago, Chicago, Illinois, 60637; Department of Neurosciences, University of California at San Diego, La Jolla, California, 92093; Department of Neuropathology and Neuroscience, University of Tokyo, Tokyo, Japan; Laboratory of Molecular and Cellular Neuroscience, Rockefeller University, New York, New York, 10021
John Christianson: Department of Neurobiology, Pharmacology, and Physiology, University of Chicago, Chicago, Illinois, 60637; Committee on Neurobiology, University of Chicago, Chicago, Illinois, 60637; Department of Neurosciences, University of California at San Diego, La Jolla, California, 92093; Department of Neuropathology and Neuroscience, University of Tokyo, Tokyo, Japan; Laboratory of Molecular and Cellular Neuroscience, Rockefeller University, New York, New York, 10021
Christian Wanamaker: Department of Neurobiology, Pharmacology, and Physiology, University of Chicago, Chicago, Illinois, 60637; Committee on Neurobiology, University of Chicago, Chicago, Illinois, 60637; Department of Neurosciences, University of California at San Diego, La Jolla, California, 92093; Department of Neuropathology and Neuroscience, University of Tokyo, Tokyo, Japan; Laboratory of Molecular and Cellular Neuroscience, Rockefeller University, New York, New York, 10021
LaShaunda T. King: Department of Neurobiology, Pharmacology, and Physiology, University of Chicago, Chicago, Illinois, 60637; Committee on Neurobiology, University of Chicago, Chicago, Illinois, 60637; Department of Neurosciences, University of California at San Diego, La Jolla, California, 92093; Department of Neuropathology and Neuroscience, University of Tokyo, Tokyo, Japan; Laboratory of Molecular and Cellular Neuroscience, Rockefeller University, New York, New York, 10021
Margaret L. Veselits: Department of Neurobiology, Pharmacology, and Physiology, University of Chicago, Chicago, Illinois, 60637; Committee on Neurobiology, University of Chicago, Chicago, Illinois, 60637; Department of Neurosciences, University of California at San Diego, La Jolla, California, 92093; Department of Neuropathology and Neuroscience, University of Tokyo, Tokyo, Japan; Laboratory of Molecular and Cellular Neuroscience, Rockefeller University, New York, New York, 10021
Taisuke Tomita: Department of Neurobiology, Pharmacology, and Physiology, University of Chicago, Chicago, Illinois, 60637; Committee on Neurobiology, University of Chicago, Chicago, Illinois, 60637; Department of Neurosciences, University of California at San Diego, La Jolla, California, 92093; Department of Neuropathology and Neuroscience, University of Tokyo, Tokyo, Japan; Laboratory of Molecular and Cellular Neuroscience, Rockefeller University, New York, New York, 10021
Laura Gasparini: Department of Neurobiology, Pharmacology, and Physiology, University of Chicago, Chicago, Illinois, 60637; Committee on Neurobiology, University of Chicago, Chicago, Illinois, 60637; Department of Neurosciences, University of California at San Diego, La Jolla, California, 92093; Department of Neuropathology and Neuroscience, University of Tokyo, Tokyo, Japan; Laboratory of Molecular and Cellular Neuroscience, Rockefeller University, New York, New York, 10021
Takeshi Iwatsubo: Department of Neurobiology, Pharmacology, and Physiology, University of Chicago, Chicago, Illinois, 60637; Committee on Neurobiology, University of Chicago, Chicago, Illinois, 60637; Department of Neurosciences, University of California at San Diego, La Jolla, California, 92093; Department of Neuropathology and Neuroscience, University of Tokyo, Tokyo, Japan; Laboratory of Molecular and Cellular Neuroscience, Rockefeller University, New York, New York, 10021
Huaxi Xu: Department of Neurobiology, Pharmacology, and Physiology, University of Chicago, Chicago, Illinois, 60637; Committee on Neurobiology, University of Chicago, Chicago, Illinois, 60637; Department of Neurosciences, University of California at San Diego, La Jolla, California, 92093; Department of Neuropathology and Neuroscience, University of Tokyo, Tokyo, Japan; Laboratory of Molecular and Cellular Neuroscience, Rockefeller University, New York, New York, 10021
William N. Green: Department of Neurobiology, Pharmacology, and Physiology, University of Chicago, Chicago, Illinois, 60637; Committee on Neurobiology, University of Chicago, Chicago, Illinois, 60637; Department of Neurosciences, University of California at San Diego, La Jolla, California, 92093; Department of Neuropathology and Neuroscience, University of Tokyo, Tokyo, Japan; Laboratory of Molecular and Cellular Neuroscience, Rockefeller University, New York, New York, 10021
Edward H. Koo: Department of Neurobiology, Pharmacology, and Physiology, University of Chicago, Chicago, Illinois, 60637; Committee on Neurobiology, University of Chicago, Chicago, Illinois, 60637; Department of Neurosciences, University of California at San Diego, La Jolla, California, 92093; Department of Neuropathology and Neuroscience, University of Tokyo, Tokyo, Japan; Laboratory of Molecular and Cellular Neuroscience, Rockefeller University, New York, New York, 10021
Gopal Thinakaran: Department of Neurobiology, Pharmacology, and Physiology, University of Chicago, Chicago, Illinois, 60637; Committee on Neurobiology, University of Chicago, Chicago, Illinois, 60637; Department of Neurosciences, University of California at San Diego, La Jolla, California, 92093; Department of Neuropathology and Neuroscience, University of Tokyo, Tokyo, Japan; Laboratory of Molecular and Cellular Neuroscience, Rockefeller University, New York, New York, 10021

Journal volume & issue: Vol. 11, no. 1
pp. 64 – 82

Abstract

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Presenilin 1 (PS1) and presenilin 2 play a critical role in the γ-secretase processing of amyloid precursor protein (APP) and Notch1. Here, we investigate maturation and intracellular trafficking of APP and other membrane proteins in cells expressing an experimental PS1 deletion mutant (ΔM1,2). Stable expression of ΔM1,2 impairs γ-secretase processing of Notch1 and delays Aβ secretion. Kinetic studies show enhanced O-glycosylation and sialylation of holo-APP and marked accumulation of APP COOH-terminal fragments (CTFs). Surface biotinylation, live staining, and trafficking studies show increased surface accumulation of holo-APP and CTFs in ΔM1,2 cells resulting from enhanced surface delivery of newly synthesized APP. Expression of a loss-of-function PS1 mutant (D385A) or incubation of cells with γ-secretase inhibitors also increases surface levels of holo-APP and CTFs. In contrast to APP, glycosylation and surface accumulation of another type I membrane protein, nicastrin, are markedly reduced in ΔM1,2 cells. Finally, expression of ΔM1,2 results in the increased assembly and surface expression of nicotinic acetylcholine receptors, illustrating that PS1's influence on protein trafficking extends beyond APP and other type I membrane protein substrates of γ-secretase. Collectively, our findings provide evidence that PS1 regulates the glycosylation and intracellular trafficking of APP and select membrane proteins.

Published in Neurobiology of Disease

ISSN: 0969-9961 (Print); 1095-953X (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Medicine: Internal medicine: Neurosciences. Biological psychiatry. Neuropsychiatry
Website: https://www.journals.elsevier.com/neurobiology-of-disease

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