Article

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

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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    • "Transfected cells were observed after 48 to 72 h. To independently examine functional deficits arising from expression of the mutated presenilin 1 (PS1 M146V ), cultured normal rat astrocytes were co-transfected with the plasmid encoding ANP.emd and the plasmid encoding PS1 M146V (kindly provided by Dr. Ilya Bezprozvanny, UT Southwestern Medical Center at Dallas, Dallas, TX (Tu et al., 2006)), while control cells were transfected with pANP.emd alone (1 mg/mL). "

    Full-text · Article · Feb 2016 · Glia
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    • "First, the presenilins interact with several proteins functionally involved in calcium signalling , including sorcin, calmodulin, calsenilin, calmyrin and calpain [104] [105] [106]. It was next proposed that presenilin holoproteins act as passive Ca 2+ channels in the ER and those PS FAD mutations alter channel conductance [93]. In an elegant mutagenesis study it was subsequently demonstrated that the hydrophilic catalytic cavity of PS1 facilitates the formation of a calcium leak conductance pore [107]. "
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    ABSTRACT: The presenilins are the catalytic subunit of the membrane-embedded tetrameric γ-secretase protease complexes. More that 90 transmembrane proteins have been reported to be γ-secretase substrates, including the widely studied amyloid precursor protein (APP) and the Notch receptor, which are precursors for the generation of amyloid-β peptides and biologically active APP intracellular domain (AICD) and Notch intracellular domain (NICD). The diversity of γ-secretase substrates highlights the importance of presenilin-dependent γ-secretase protease activities as a regulatory mechanism in a range of biological systems. However, there is also a growing body of evidence that supports the existence of γ-secretase-independent functions for the presenilins in the regulation and progression of an array of cell signalling pathways. In this review, we will present an overview of current literature that proposes evolutionarily conserved presenilin functions outside of the γ-secretase complex, with a focus on the suggested role of the presenilins in the regulation of Wnt/β-catenin signalling, protein trafficking and degradation, calcium homeostasis and apoptosis.
    Full-text · Article · Oct 2015 · Cellular Signalling
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    • "Transfected cells were observed after 48 to 72 h. To independently examine functional deficits arising from expression of the mutated presenilin 1 (PS1 M146V ), cultured normal rat astrocytes were co-transfected with the plasmid encoding ANP.emd and the plasmid encoding PS1 M146V (kindly provided by Dr. Ilya Bezprozvanny, UT Southwestern Medical Center at Dallas, Dallas, TX (Tu et al., 2006)), while control cells were transfected with pANP.emd alone (1 mg/mL). "
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    ABSTRACT: In the brain, astrocytes provide metabolic and trophic support to neurones. Failure in executing astroglial homeostatic functions may contribute to the initiation and propagation of diseases, including Alzheimer disease (AD), characterized by a progressive loss of neurones over years. Here, we examined whether astrocytes from a mice model of AD isolated in the presymptomatic phase of the disease exhibit alterations in vesicle traffic, vesicular peptide release and purinergic calcium signaling. In cultured astrocytes isolated from a newborn wild-type (wt) and 3xTg-AD mouse, secretory vesicles and acidic endosomes/lysosomes were labeled by transfection with plasmid encoding atrial natriuretic peptide tagged with mutant green fluorescent protein (ANP.emd) and by LysoTracker, respectively. The intracellular Ca(2+) concentration ([Ca(2+) ]i ) was monitored with Fluo-2 and visualized by confocal microscopy. In comparison with controls, spontaneous mobility of ANP- and LysoTracker-labeled vesicles was diminished in 3xTg-AD astrocytes; the track length (TL), maximal displacement (MD) and directionality index (DI) were all reduced in peptidergic vesicles and in endosomes/lysosomes (P < 0.001), as was the ATP-evoked attenuation of vesicle mobility. Similar impairment of peptidergic vesicle trafficking was observed in wt rat astrocytes transfected to express mutated presenilin 1 (PS1M146V ). The ATP-evoked ANP discharge from single vesicles was less efficient in 3xTg-AD and PS1M146V -expressing astrocytes than in respective wt controls (P < 0.05). Purinergic stimulation evoked biphasic and oscillatory [Ca(2+) ]i responses; the latter were less frequent (P < 0.001) in 3xTg-AD astrocytes. Expression of PS1M146V in astrocytes impairs vesicle dynamics and reduces evoked secretion of the signaling molecule ANP; both may contribute to the development of AD. GLIA 2015.
    Full-text · Article · Oct 2015 · Glia
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