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Title: Presenilins form ER Ca2+ leak channels, a function disrupted by familial Alzheimer's disease-linked mutations
Authors: Tu, Huiping
Nelson, Omar
Bezprozvanny, Arseny
Wang, Zhengnan
Lee, Sheu-Fen
Hao, Yi-Heng
Serneels, Lutgarde
De Strooper, Bart
Yu, Gang
Bezprozvanny, Ilya # ×
Issue Date: Sep-2006
Publisher: MIT Press
Series Title: Cell vol:126 issue:5 pages:981-93
Abstract: Alzheimer's disease (AD) is a progressive and irreversible neurodegenerative disorder. Mutations in presenilins 1 and 2 (PS1 and PS2) account for approximately 40% of familial AD (FAD) cases. FAD mutations and genetic deletions of presenilins have been associated with calcium (Ca(2+)) signaling abnormalities. We demonstrate that wild-type presenilins, but not PS1-M146V and PS2-N141I FAD mutants, can form low-conductance divalent-cation-permeable ion channels in planar lipid bilayers. In experiments with PS1/2 double knockout (DKO) mouse embryonic fibroblasts (MEFs), we find that presenilins account for approximately 80% of passive Ca(2+) leak from the endoplasmic reticulum. Deficient Ca(2+) signaling in DKO MEFs can be rescued by expression of wild-type PS1 or PS2 but not by expression of PS1-M146V or PS2-N141I mutants. The ER Ca(2+) leak function of presenilins is independent of their gamma-secretase activity. Our data suggest a Ca(2+) signaling function for presenilins and provide support for the "Ca(2+) hypothesis of AD."
URI: 
ISSN: 0092-8674
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Molecular Genetics Section (-)
Department of Human Genetics - miscellaneous
× corresponding author
# (joint) last author

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