Restricted Location of PSEN2/gamma-Secretase Determines Substrate Specificity and Generates an Intracellular A beta Pool

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 WaelkensGuriqbal S. Basi, Mark Mercken, Marc Vooijs, Mathieu Bollen, Joost Schymkowitz, Frederic Rousseau, Juan S. Bonifacino, Guillaume Van Niel, Bart De Strooper, Wim Annaert*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

172 Citations (Web of Science)


gamma-Secretases are a family of intramembrane-cleaving proteases involved in various signaling pathways and diseases, including Alzheimer's disease (AD). Cells co-express differing gamma-secretase complexes, including two homologous presenilins (PSENs). We examined the significance of this heterogeneity and identified a unique motif in PSEN2 that directs this gamma-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 A beta that contains longer A beta; familial AD (FAD)-associated mutations in PSEN2 increased the levels of longer A beta 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 gamma-secretases determines substrate specificity, while FAD-causing mutations strongly enhance accumulation of aggregation-prone A beta 42 in intracellular acidic compartments. The findings reveal potentially important roles for specific intracellular, localized reactions contributing to AD pathogenesis.
Original languageEnglish
Pages (from-to)193-208
Issue number1
Publication statusPublished - 30 Jun 2016

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