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Presenilins Form ER Ca2+ Leak Channels, a Function Disrupted by Familial Alzheimer's Disease-Linked Mutations

Department of Physiology, UT Southwestern Medical Center at Dallas, Dallas, TX 75390, USA.
Cell (Impact Factor: 33.12). 10/2006; 126(5):981-93. DOI: 10.1016/j.cell.2006.06.059
Source: PubMed

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."

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    • "The Ca 2+ permeability of the presenilins, gene mutations of which have been linked to familial Alzheimer diseases, has been extensively documented in several studies (Tu et al. 2006; Nelson et al. 2010; Zhang et al. 2010). In these reports, a speculative role for presenilins as participants in ER Ca 2+ leak has been proposed although these conclusions are disputed (Shilling et al. 2012). "
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    • "Presenilin proteins have also been shown to have a non-proteolytic function as a scaffold for the regulation of glycogen synthase kinase 3b (GSK3b)-dependent b-catenin phosphorylation (Kang et al., 1999; Kang et al., 2002). Finally, presenilin proteins have also been implicated in altered calcium signalling (Tu et al., 2006) through an unknown mechanism. "
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