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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    • "APs serve important functions in some important metabolic processes and in many diseases. In vertebrates, APs participate in various physiological and pathological processes, such as the rennin in hypertension and beta-secretase in Alzheimer's disease (Tu et al., 2006). In plants, APs have roles in senescence, stress responses and fertilization as well as in pathogen defense (Simoes and Faro, 2004). "
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    Gene 01/2015; 559(1). DOI:10.1016/j.gene.2015.01.020 · 2.08 Impact Factor
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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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    The Journal of Physiology 10/2014; 593(15). DOI:10.1113/jphysiol.2014.281881 · 4.54 Impact Factor
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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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