Article

Familial Alzheimer disease-linked mutations specifically disrupt Ca2+ leak function of presenilin 1.

Department of Physiology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, USA.
Journal of Clinical Investigation (Impact Factor: 13.77). 06/2007; 117(5):1230-9. DOI: 10.1172/JCI30447
Source: PubMed

ABSTRACT Mutations in presenilins are responsible for approximately 40% of all early-onset familial Alzheimer disease (FAD) cases in which a genetic cause has been identified. In addition, a number of mutations in presenilin-1 (PS1) have been suggested to be associated with the occurrence of frontal temporal dementia (FTD). Presenilins are highly conserved transmembrane proteins that support cleavage of the amyloid precursor protein by gamma-secretase. Recently, we discovered that presenilins also function as passive ER Ca(2+) leak channels. Here we used planar lipid bilayer reconstitution assays and Ca(2+) imaging experiments with presenilin-null mouse embryonic fibroblasts to analyze ER Ca(2+) leak function of 6 FAD-linked PS1 mutants and 3 known FTD-associated PS1 mutants. We discovered that L166P, A246E, E273A, G384A, and P436Q FAD mutations in PS1 abolished ER Ca(2+) leak function of PS1. In contrast, A79V FAD mutation or FTD-associated mutations (L113P, G183V, and Rins352) did not appear to affect ER Ca(2+) leak function of PS1 in our experiments. We validated our findings in Ca(2+) imaging experiments with primary fibroblasts obtained from an FAD patient possessing mutant PS1-A246E. Our results indicate that many FAD mutations in presenilins are loss-of-function mutations affecting ER Ca(2+) leak activity. In contrast, none of the FTD-associated mutations affected ER Ca(2+) leak function of PS1, indicating that the observed effects are disease specific. Our observations are consistent with the potential role of disturbed Ca(2+) homeostasis in Alzheimer disease pathogenesis.

Download full-text

Full-text

Available from: Ilya Bezprozvanny, Jul 04, 2015
0 Followers
 · 
95 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The endoplasmic reticulum (ER) is a dynamic intracellular organelle with multiple functions essential for cellular homeostasis, development, and stress responsiveness. In response to cellular stress, a well-established signaling cascade, the unfolded protein response (UPR), is activated. This intricate mechanism is an important means of re-establishing cellular homeostasis and alleviating the inciting stress. Now, emerging evidence has demonstrated that the UPR influences cellular metabolism through diverse mechanisms, including calcium and lipid transfer, raising the prospect of involvement of these processes in the pathogenesis of disease, including neurodegeneration, cancer, diabetes mellitus and cardiovascular disease. Here, we review the distinct functions of the ER and UPR from a metabolic point of view, highlighting their association with prevalent pathologies.
    International review of cell and molecular biology 01/2013; 301:215-90. DOI:10.1016/B978-0-12-407704-1.00005-1
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The kinetics of single-amperometric exocytotic events has been measured in chromaffin cells of C57 mice and in an APP/PS1 mouse model of Alzheimer's disease (AD). K(+) depolarisation causes a burst of spikes that indicate the quantal release of the single-vesicle content of catecholamine. The kinetic analysis of 278 spikes from 10 control cells and 520 spikes from 18 APP/PS1 cells shows the following features of the latter compared with the former: (i) 45% lower t(1/2); (ii) 60% smaller quantal size; (iii) 50% lower decay time. Spike feet also showed 60% smaller quantal size. Immunofluorescence and thioflavin staining showed no amyloid β (Aβ) burden in adrenal medulla slices of APP/PS1 mice that however exhibited dense Aβ plaques in the cortex and hippocampus. Furthermore, acetylcholinesterase staining of adrenal medulla indicated no apparent differences in the innervation by splanchnic cholinergic nerve terminals of chromaffin cells from control and APP/PS1 mice. This is the first report identifying subtle differences in the last steps of exocytosis that could be an indication of synaptic dysfunction of the secretory machinery not linked to Aβ burden in AD.
    Biochemical and Biophysical Research Communications 10/2012; 428(4). DOI:10.1016/j.bbrc.2012.10.082
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Mutations in presenilins (PS), transmembrane proteins encoding the catalytic subunit of γ-secretase, result in familial Alzheimer's disease (FAD). Several studies have identified lysosomal defects in cells lacking PS or expressing FAD-associated PS mutations, which have been previously attributed to a function for PS in lysosomal acidification. Now, in this issue, Coen et al. (2012. J. Cell Biol. http://dx.doi.org/10.1083/jcb.201201076) provide a series of results that challenge this idea and propose instead that presenilins play a role in calcium-mediated lysosomal fusion.
    The Journal of Cell Biology 07/2012; 198(1):7-10. DOI:10.1083/jcb.201206003