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 Waelkens; Guriqbal S. Basi; Mark Mercken; Marc Vooijs; Mathieu Bollen; Joost Schymkowitz; Frederic Rousseau; Juan S. Bonifacino; Guillaume Van Niel; Bart De Strooper; Wim Annaert

doi:10.1016/j.cell.2016.05.020

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 journal › Article › Academic › peer-review

Abstract

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 language	English
Pages (from-to)	193-208
Journal	Cell
Volume	166
Issue number	1
DOIs	https://doi.org/10.1016/j.cell.2016.05.020
Publication status	Published - 30 Jun 2016

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Sannerud, R., Esselens, C., Ejsmont, P., Mattera, R., Rochin, L., Tharkeshwar, A. K., De Baets, G., De Wever, V., Habets, R., Baert, V., Vermeire, W., Michiels, C., Groot, A. J., Wouters, R., Dillen, K., Vints, K., Baatsen, P., Munck, S., Derua, R., ... Annaert, W. (2016). Restricted Location of PSEN2/gamma-Secretase Determines Substrate Specificity and Generates an Intracellular A beta Pool. Cell, 166(1), 193-208. https://doi.org/10.1016/j.cell.2016.05.020

@article{ab9ea63a353346cf8515f0531f7965bb,

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

abstract = "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.",

author = "Ragna Sannerud and Cary Esselens and Paulina Ejsmont and Rafael Mattera and Leila Rochin and Tharkeshwar, {Arun Kumar} and {De Baets}, Greet and {De Wever}, Veerle and Roger Habets and Veerle Baert and Wendy Vermeire and Christine Michiels and Groot, {Arjan J.} and Rosanne Wouters and Katleen Dillen and Katlijn Vints and Pieter Baatsen and Sebastian Munck and Rita Derua and Etienne Waelkens and Basi, {Guriqbal S.} and Mark Mercken and Marc Vooijs and Mathieu Bollen and Joost Schymkowitz and Frederic Rousseau and Bonifacino, {Juan S.} and {Van Niel}, Guillaume and {De Strooper}, Bart and Wim Annaert",

year = "2016",

month = jun,

day = "30",

doi = "10.1016/j.cell.2016.05.020",

language = "English",

volume = "166",

pages = "193--208",

journal = "Cell",

issn = "0092-8674",

publisher = "Cell Press",

number = "1",

}

Sannerud, R, Esselens, C, Ejsmont, P, Mattera, R, Rochin, L, Tharkeshwar, AK, De Baets, G, De Wever, V, Habets, R, Baert, V, Vermeire, W, Michiels, C, Groot, AJ, Wouters, R, Dillen, K, Vints, K, Baatsen, P, Munck, S, Derua, R, Waelkens, E, Basi, GS, Mercken, M, Vooijs, M, Bollen, M, Schymkowitz, J, Rousseau, F, Bonifacino, JS, Van Niel, G, De Strooper, B & Annaert, W 2016, 'Restricted Location of PSEN2/gamma-Secretase Determines Substrate Specificity and Generates an Intracellular A beta Pool', Cell, vol. 166, no. 1, pp. 193-208. https://doi.org/10.1016/j.cell.2016.05.020

TY - JOUR

T1 - Restricted Location of PSEN2/gamma-Secretase Determines Substrate Specificity and Generates an Intracellular A beta Pool

AU - Sannerud, Ragna

AU - Esselens, Cary

AU - Ejsmont, Paulina

AU - Mattera, Rafael

AU - Rochin, Leila

AU - Tharkeshwar, Arun Kumar

AU - De Baets, Greet

AU - De Wever, Veerle

AU - Habets, Roger

AU - Baert, Veerle

AU - Vermeire, Wendy

AU - Michiels, Christine

AU - Groot, Arjan J.

AU - Wouters, Rosanne

AU - Dillen, Katleen

AU - Vints, Katlijn

AU - Baatsen, Pieter

AU - Munck, Sebastian

AU - Derua, Rita

AU - Waelkens, Etienne

AU - Basi, Guriqbal S.

AU - Mercken, Mark

AU - Vooijs, Marc

AU - Bollen, Mathieu

AU - Schymkowitz, Joost

AU - Rousseau, Frederic

AU - Bonifacino, Juan S.

AU - Van Niel, Guillaume

AU - De Strooper, Bart

AU - Annaert, Wim

PY - 2016/6/30

Y1 - 2016/6/30

N2 - 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.

AB - 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.

U2 - 10.1016/j.cell.2016.05.020

DO - 10.1016/j.cell.2016.05.020

M3 - Article

C2 - 27293189

SN - 0092-8674

VL - 166

SP - 193

EP - 208

JO - Cell

JF - Cell

IS - 1

ER -