Familial Alzheimer disease-linked mutations specifically disrupt Ca

Department of Physiology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, USA.
Journal of Clinical Investigation (Impact Factor: 13.22). 06/2007; 117(5):1230-9. DOI: 10.1172/JCI30447
Source: PubMed


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.

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    • "Our results suggested that presenilin holoproteins function as low conductance passive ER Ca2+ leak channel, and that ER Ca2+ leak function of presenilins does not depend on their γ-secretase activity (Tu et al., 2006). Moreover, we found that some, but not all, FAD PS mutations disrupt Ca2+ leak function (Tu et al., 2006; Nelson et al., 2007, 2010), leading to the overfilling of ER with Ca2+ and exaggerated ER Ca2+ release observed in PS1/PS2 FAD mutants fibroblasts (Tu et al., 2006; Nelson et al., 2007, 2010), cultured hippocampal neurons from 3xTg AD neurons (Zhang et al., 2010b), and primary lymphoblasts from FAD patients (Nelson et al., 2010). These data suggest that mutations in presenilins directly linked to deranged Ca2+ signaling and neuronal dysfunction in AD by causing ER Ca2+ overload. "
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    ABSTRACT: Alzheimer disease (AD) is a major threat of twenty-first century that is responsible for the majority of dementia in the elderly. Development of effective AD-preventing therapies are the top priority tasks for neuroscience research. Amyloid hypothesis of AD is a dominant idea in the field, but so far all amyloid-targeting therapies have failed in clinical trials. In addition to amyloid accumulation, there are consistent reports of abnormal calcium signaling in AD neurons. AD neurons exhibit enhanced intracellular calcium (Ca(2) (+)) liberation from the endoplasmic reticulum (ER) and reduced store-operated Ca(2) (+) entry (SOC). These changes occur primarily as a result of ER Ca(2) (+) overload. We argue that normalization of intracellular Ca(2) (+) homeostasis could be a strategy for development of effective disease-modifying therapies. The current review summarizes recent data about changes in ER Ca(2) (+) signaling in AD. Ca(2) (+) channels that are discussed in the current review include: inositol trisphosphate receptors, ryanodine receptors, presenilins as ER Ca(2) (+) leak channels, and neuronal SOC channels. We discuss how function of these channels is altered in AD and how important are resulting Ca(2) (+) signaling changes for AD pathogenesis.
    Frontiers in Molecular Neuroscience 09/2013; 6:29. DOI:10.3389/fnmol.2013.00029 · 4.08 Impact Factor
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    • "Many FAD mutants (e.g. PS1M146V and PS2N141I) disrupt or abolish the Ca2+ leak channel activity, leading to overload of Ca2+ in ER [151]. It has been reported that presenilin transmembrane domain 7 and 9 contribute to the forming of the ion conductance pore, and transmembrane water-filled catalytic cavity of presenilin constitutes the Ca2+ leak channel [152]. "
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    ABSTRACT: Presenilins (PSs) are the catalytic core of gamma-secretase complex. However, the mechanism of FAD-associated PS mutations in AD pathogenesis still remains elusive. Here we review the general biology and mechanism of gamma-secretase and focus on the catalytic components -- presenilins and their biological functions and contributions to the AD pathogenesis. The functions of presenilins are divided into gamma-secretase dependent and gamma-secretase independent ones. The gamma-secretase dependent functions of presenilins are exemplified by the sequential cleavages in the processing of APP and Notch; the gamma-secretase independent functions of presenilins include stabilizing beta-catenin in Wnt signaling pathway, regulating calcium homeostasis and their interaction with synaptic transmission.
    Translational Neurodegeneration 07/2013; 2(1):15. DOI:10.1186/2047-9158-2-15
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    • "Many FAD mutations in presenilins disrupt the ER Ca2+ leak function and result in elevated ER Ca2+ levels [160,165-167,171] and impaired store-operated Ca2+ entry [166,171,172]. As discussed above, increased ER Ca2+ levels are one of the signature features of aging neurons [146]. "
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    ABSTRACT: Most neurons are born with the potential to live for the entire lifespan of the organism. In addition, neurons are highly polarized cells with often long axons, extensively branched dendritic trees and many synaptic contacts. Longevity together with morphological complexity results in a formidable challenge to maintain synapses healthy and functional. This challenge is often evoked to explain adult-onset degeneration in numerous neurodegenerative disorders that result from otherwise divergent causes. However, comparably little is known about the basic cell biological mechanisms that keep normalsynapses alive and functional in the first place. How the basic maintenance mechanisms are related to slow adult-onset degeneration in different diseasesis largely unclear. In this review we focus on two basic and interconnected cell biological mechanisms that are required for synaptic maintenance: endomembrane recycling and calcium (Ca2+) homeostasis. We propose that subtle defects in these homeostatic processes can lead to late onset synaptic degeneration. Moreover, the same basic mechanisms are hijacked, impaired or overstimulated in numerous neurodegenerative disorders. Understanding the pathogenesis of these disorders requires an understanding of both the initial cause of the disease and the on-going changes in basic maintenance mechanisms. Here we discuss the mechanisms that keep synapses functional over long periods of time with the emphasis on their role in slow adult-onset neurodegeneration.
    Molecular Neurodegeneration 07/2013; 8(1):23. DOI:10.1186/1750-1326-8-23 · 6.56 Impact Factor
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