Restricted Location of PSEN2/γ-Secretase Determines Substrate Specificity and Generates an Intracellular Aβ Pool.
γ-Secretases are a family of intramembrane-cleaving proteases involved in various signaling pathways and diseases, including Alzheimer's disease (AD). Cells co-express differing γ-secretase complexes, including two homologous presenilins (PSENs). We examined the significance of this heterogeneity and identified a unique motif in PSEN2 that directs this γ-secretase to late endosomes/lysosomes via a phosphorylation-dependent interaction with the AP-1 adaptor complex. Accordingly, PSEN2 selectively cleaves late endosomal/lysosomal localized substrates and generates the prominent pool of intracellular Aβ that contains longer Aβ; familial AD (FAD)-associated mutations in PSEN2 increased the levels of longer Aβ further. Moreover, a subset of FAD mutants in PSEN1, normally more broadly distributed in the cell, phenocopies PSEN2 and shifts its localization to late endosomes/lysosomes. Thus, localization of γ-secretases determines substrate specificity, while FAD-causing mutations strongly enhance accumulation of aggregation-prone Aβ42 in intracellular acidic compartments. The findings reveal potentially important roles for specific intracellular, localized reactions contributing to AD pathogenesis.
VIB Center for the Biology of Disease, KU Leuven, 3000 Leuven, Belgium; Department of Human Genetics, KU Leuven, 3000 Leuven, Belgium.
Ragna
R
Sannerud
VIB Center for the Biology of Disease, KU Leuven, 3000 Leuven, Belgium; Department of Human Genetics, KU Leuven, 3000 Leuven, Belgium.
Cary
C
Esselens
VIB Center for the Biology of Disease, KU Leuven, 3000 Leuven, Belgium; Department of Human Genetics, KU Leuven, 3000 Leuven, Belgium.
Paulina
P
Ejsmont
Cell Biology and Neurobiology Branch, NICHD, NIH, Bethesda, MD 20892, USA.
Rafael
R
Mattera
Institut Curie, PSL Research University, CNRS, UMR 144, Paris 75005, France; CNRS, UMR 144, Paris 75005, France.
Leila
L
Rochin
VIB Center for the Biology of Disease, KU Leuven, 3000 Leuven, Belgium; Department of Human Genetics, KU Leuven, 3000 Leuven, Belgium.
Arun Kumar
AK
Tharkeshwar
VIB Switch Laboratory, KU Leuven, 3000 Leuven, Belgium; Department of Cellular and Molecular Medicine, KU Leuven, 3000 Leuven, Belgium.
Greet
G
De Baets
Department of Cellular and Molecular Medicine, KU Leuven, 3000 Leuven, Belgium.
Veerle
V
De Wever
Department of Radiotherapy (MAASTRO)/GROW, Maastricht University, 6211 Maastricht, the Netherlands.
Roger
R
Habets
VIB Center for the Biology of Disease, KU Leuven, 3000 Leuven, Belgium; Department of Human Genetics, KU Leuven, 3000 Leuven, Belgium.
Veerle
V
Baert
VIB Center for the Biology of Disease, KU Leuven, 3000 Leuven, Belgium; Department of Human Genetics, KU Leuven, 3000 Leuven, Belgium.
Wendy
W
Vermeire
VIB Center for the Biology of Disease, KU Leuven, 3000 Leuven, Belgium; Department of Human Genetics, KU Leuven, 3000 Leuven, Belgium.
Christine
C
Michiels
Department of Radiotherapy (MAASTRO)/GROW, Maastricht University, 6211 Maastricht, the Netherlands.
Arjan J
AJ
Groot
VIB Center for the Biology of Disease, KU Leuven, 3000 Leuven, Belgium; Department of Human Genetics, KU Leuven, 3000 Leuven, Belgium.
Rosanne
R
Wouters
VIB Center for the Biology of Disease, KU Leuven, 3000 Leuven, Belgium; Department of Human Genetics, KU Leuven, 3000 Leuven, Belgium.
Katleen
K
Dillen
VIB BioImaging Core, 3000 Leuven, Belgium.
Katlijn
K
Vints
VIB BioImaging Core, 3000 Leuven, Belgium.
Pieter
P
Baatsen
VIB BioImaging Core, 3000 Leuven, Belgium.
Sebastian
S
Munck
Department of Cellular and Molecular Medicine, KU Leuven, 3000 Leuven, Belgium.
Rita
R
Derua
Department of Cellular and Molecular Medicine, KU Leuven, 3000 Leuven, Belgium.
Etienne
E
Waelkens
Avalanche Biotechnology, Menlo Park, CA 94025, USA.
Guriqbal S
GS
Basi
Janssen Pharmaceutica, 2340 Beerse, Belgium.
Mark
M
Mercken
Department of Radiotherapy (MAASTRO)/GROW, Maastricht University, 6211 Maastricht, the Netherlands.
Marc
M
Vooijs
Department of Cellular and Molecular Medicine, KU Leuven, 3000 Leuven, Belgium.
Mathieu
M
Bollen
VIB Switch Laboratory, KU Leuven, 3000 Leuven, Belgium; Department of Cellular and Molecular Medicine, KU Leuven, 3000 Leuven, Belgium.
Joost
J
Schymkowitz
VIB Switch Laboratory, KU Leuven, 3000 Leuven, Belgium; Department of Cellular and Molecular Medicine, KU Leuven, 3000 Leuven, Belgium.
Frederic
F
Rousseau
Cell Biology and Neurobiology Branch, NICHD, NIH, Bethesda, MD 20892, USA.
Juan S
JS
Bonifacino
Institut Curie, PSL Research University, CNRS, UMR 144, Paris 75005, France; CNRS, UMR 144, Paris 75005, France.
Guillaume
G
Van Niel
VIB Center for the Biology of Disease, KU Leuven, 3000 Leuven, Belgium; Department of Human Genetics, KU Leuven, 3000 Leuven, Belgium; Department of Molecular Neuroscience, UCL Institute of Neurology, London WC1E 6BT, UK.
Bart
B
De Strooper
VIB Center for the Biology of Disease, KU Leuven, 3000 Leuven, Belgium; Department of Human Genetics, KU Leuven, 3000 Leuven, Belgium. Electronic address: wim.annaert@cme.vib-kuleuven.be.
Wim
W
Annaert
D033961:Adaptor Protein Complex 1 / Q000378:metabolism; D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D020816:Amino Acid Motifs; D053829:Amyloid Precursor Protein Secretases / Q000032:analysis* / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D045744:Cell Line, Tumor; D011992:Endosomes / Q000737:chemistry; D006801:Humans; D008247:Lysosomes / Q000737:chemistry; D051379:Mice; D010446:Peptide Fragments / Q000378:metabolism*; D053764:Presenilin-1 / Q000032:analysis / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D053766:Presenilin-2 / Q000032:analysis* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D051381:Rats; D013379:Substrate Specificity
D033961:Adaptor Protein Complex 1; D016229:Amyloid beta-Peptides; C508853:PSEN1 protein, human; C508861:PSEN2 protein, human; D010446:Peptide Fragments; D053764:Presenilin-1; D053766:Presenilin-2; C075222:amyloid beta-protein (1-42); D053829:Amyloid Precursor Protein Secretases