1. Restricted Location of PSEN2/γ-Secretase Determines Substrate Specificity and Generates an Intracellular Aβ Pool
- Author
-
Ragna, Sannerud, Cary, Esselens, Paulina, Ejsmont, Rafael, Mattera, Leila, Rochin, Arun Kumar, Tharkeshwar, Greet, De Baets, Veerle, De Wever, Roger, Habets, Veerle, Baert, Wendy, Vermeire, Christine, Michiels, Arjan J, Groot, Rosanne, Wouters, Katleen, Dillen, Katlijn, Vints, Pieter, Baatsen, Sebastian, Munck, Rita, Derua, Etienne, Waelkens, Guriqbal S, Basi, Mark, Mercken, Marc, Vooijs, Mathieu, Bollen, Joost, Schymkowitz, Frederic, Rousseau, Juan S, Bonifacino, Guillaume, Van Niel, Bart, De Strooper, and Wim, Annaert
- Subjects
Amyloid beta-Peptides ,Adaptor Protein Complex 1 ,Amino Acid Motifs ,Endosomes ,Peptide Fragments ,Rats ,Substrate Specificity ,Mice ,Alzheimer Disease ,Cell Line, Tumor ,Presenilin-2 ,Presenilin-1 ,Animals ,Humans ,Amyloid Precursor Protein Secretases ,Lysosomes - 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. publisher: Elsevier articletitle: Restricted Location of PSEN2/γ-Secretase Determines Substrate Specificity and Generates an Intracellular Aβ Pool journaltitle: Cell articlelink: http://dx.doi.org/10.1016/j.cell.2016.05.020 content_type: article copyright: © 2016 Elsevier Inc. ispartof: Cell vol:166 issue:1 pages:193-208 ispartof: location:United States status: published
- Published
- 2016