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Cell. 2016 Jun 30;166(1):193-208. doi: 10.1016/j.cell.2016.05.020. Epub 2016 Jun 9.

Restricted Location of PSEN2/γ-Secretase Determines Substrate Specificity and Generates an Intracellular Aβ Pool.

Author information

1
VIB Center for the Biology of Disease, KU Leuven, 3000 Leuven, Belgium; Department of Human Genetics, KU Leuven, 3000 Leuven, Belgium.
2
Cell Biology and Neurobiology Branch, NICHD, NIH, Bethesda, MD 20892, USA.
3
Institut Curie, PSL Research University, CNRS, UMR 144, Paris 75005, France; CNRS, UMR 144, Paris 75005, France.
4
VIB Switch Laboratory, KU Leuven, 3000 Leuven, Belgium; Department of Cellular and Molecular Medicine, KU Leuven, 3000 Leuven, Belgium.
5
Department of Cellular and Molecular Medicine, KU Leuven, 3000 Leuven, Belgium.
6
Department of Radiotherapy (MAASTRO)/GROW, Maastricht University, 6211 Maastricht, the Netherlands.
7
VIB BioImaging Core, 3000 Leuven, Belgium.
8
Avalanche Biotechnology, Menlo Park, CA 94025, USA.
9
Janssen Pharmaceutica, 2340 Beerse, Belgium.
10
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.
11
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.

Abstract

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.

PMID:
27293189
DOI:
10.1016/j.cell.2016.05.020
[Indexed for MEDLINE]
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