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: 32.24). 10/2006; 126(5):981-93. DOI: 10.1016/j.cell.2006.06.059
Source: PubMed


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."

Download full-text


Available from: Bart De Strooper, Oct 07, 2015
40 Reads
    • "Presenilin 1 plays an important role in Ca 2+ homeostasis and autophagy/lysosomal protein degradation, beyond its wellstudied catalytic role as part of g-secretase (Lee et al., 2010; Tu et al., 2006). However, the relationship between two major g-secretase independent functions of PS1, namely maintenance of Ca 2+ homeostasis and lysosomal proteolysis, is poorly understood. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Presenilin 1 (PS1) deletion or Alzheimer's disease (AD)-linked mutations disrupt lysosomal acidification and proteolysis, which inhibits autophagy. Here, we establish that this phenotype stems from impaired glycosylation and instability of vATPase V0a1 subunit, causing deficient lysosomal vATPase assembly and function. We further demonstrate that elevated lysosomal pH in Presenilin 1 knockout (PS1KO) cells induces abnormal Ca(2+) efflux from lysosomes mediated by TRPML1 and elevates cytosolic Ca(2+). In WT cells, blocking vATPase activity or knockdown of either PS1 or the V0a1 subunit of vATPase reproduces all of these abnormalities. Normalizing lysosomal pH in PS1KO cells using acidic nanoparticles restores normal lysosomal proteolysis, autophagy, and Ca(2+) homeostasis, but correcting lysosomal Ca(2+) deficits alone neither re-acidifies lysosomes nor reverses proteolytic and autophagic deficits. Our results indicate that vATPase deficiency in PS1 loss-of-function states causes lysosomal/autophagy deficits and contributes to abnormal cellular Ca(2+) homeostasis, thus linking two AD-related pathogenic processes through a common molecular mechanism. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Cell Reports 08/2015; 12(9). DOI:10.1016/j.celrep.2015.07.050 · 8.36 Impact Factor
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    ABSTRACT: We performed genome-wide identifications and comparative genomic analyses of the predicted Aspartic proteases (APs) from eight parasitic flatworms, focusing on their evolution, potentials as drug targets and expression patterns. The results revealed that: i) More members of family A01 were identified from the Schistosomes than from the Cestodes; some evidence implied gene loss events along the class Cestoda, which may be related to the different ways to ingest host nutrition; ii) members in family A22 were evolutionarily highly conserved among all the parasites; iii) one retroviral-like AP in family A28 shared a highly similar predicted 3D structure with the HIV protease, implying its potential to be inhibited by HIV inhibitor-like molecules; iiii) retrotransposon-associated APs were extensively expanded among these parasites. These results implied that the evolutionary histories of some APs in these parasites might relate to adaptations to their parasitism and some APs might have potential serving as intervention targets. Copyright © 2015. Published by Elsevier B.V.
    Gene 01/2015; 559(1). DOI:10.1016/j.gene.2015.01.020 · 2.14 Impact Factor
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Intracellular Ca(2+) release through ryanodine receptor (RyR) and inositol trisphosphate receptor (IP3 R) channels is supported by a complex network of additional proteins that are located in or near the Ca(2+) release sites. In this review, we focus, not on RyR/IP3 R, but on other ion-channels that are known to be present in the sarcoplasmic/endoplasmic reticulum (ER/SR) membranes. We review their putative physiological roles and the evidence suggesting that they may support the process of intracellular Ca(2+) release, either indirectly by manipulating ionic fluxes across the ER/SR membrane or by directly interacting with a Ca(2+) -release channel. These channels rarely receive scientific attention because of the general lack of information regarding their biochemical and/or electrophysiological characteristics makes it difficult to predict their physiological roles and their impact on SR Ca(2+) fluxes. We discuss the possible role of SR K(+) channels and, in parallel, detail the known biochemical and biophysical properties of the trimeric intracellular cation (TRIC) proteins and their possible biological and pathophysiological roles in ER/SR Ca(2+) release. We summarise what is known regarding Cl(-) channels in the ER/SR and the non-selective cation channels or putative 'Ca(2+) leak channels', including mitsugumin23 (MG23), pannexins, presenilins and the transient receptor potential (TRP) channels that are distributed across ER/SR membranes but which have not yet been fully characterised functionally. © 2014 The Authors. The Journal of Physiology © 2014 The Physiological Society.
    The Journal of Physiology 10/2014; 593(15). DOI:10.1113/jphysiol.2014.281881 · 5.04 Impact Factor
Show more