Mutagenesis Mapping of the Presenilin 1 Calcium Leak Conductance Pore

Department of Physiology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390-9040, USA.
Journal of Biological Chemistry (Impact Factor: 4.57). 06/2011; 286(25):22339-47. DOI: 10.1074/jbc.M111.243063
Source: PubMed

ABSTRACT Missense mutations in presenilin 1 (PS1) and presenilin 2 (PS2) proteins are a major cause of familial Alzheimer disease. Presenilins are proteins with nine transmembrane (TM) domains that function as catalytic subunits of the γ-secretase complex responsible for the cleavage of the amyloid precursor protein and other type I transmembrane proteins. The water-filled cavity within presenilin is necessary to mediate the intramembrane proteolysis reaction. Consistent with this idea, cysteine-scanning mutagenesis and NMR studies revealed a number of water-accessible residues within TM7 and TM9 of mouse PS1. In addition to γ-secretase function, presenilins also demonstrate a low conductance endoplasmic reticulum Ca(2+) leak function, and many familial Alzheimer disease presenilin mutations impair this function. To map the potential Ca(2+) conductance pore in PS1, we systematically evaluated endoplasmic reticulum Ca(2+) leak activity supported by a series of cysteine point mutants in TM6, TM7, and TM9 of mouse PS1. The results indicate that TM7 and TM9, but not TM6, could play an important role in forming the conductance pore of PS1. These results are consistent with previous cysteine-scanning mutagenesis and NMR analyses of PS1 and provide further support for our hypothesis that the hydrophilic catalytic cavity of presenilins may also constitute a Ca(2+) conductance pore.

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Available from: Bart De Strooper, Aug 27, 2015
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    • "Such molecular alterations include increased oxidative stress, mitochondrial dysfunction , cell cycle alterations and elevated apoptosis (reviewed in [25] [26] [27] [28] [29] [30]). Well-documented impairments observed in AD lymphocytes also include changes in calcium homeostasis, particularly related to endoplasmic reticulum (ER) stress and the impaired leak channel function of mutated presenilins in ER membranes [31] [32]. Ca 2+ dyshomeostasis in AD lymphocytes also involved the effects of mutated presenilins on the IP3 receptor in the ER [33] and capacitative Ca 2+ entry mediated by Orai/Stim interactions [34]. "
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    ABSTRACT: In Alzheimer's disease (AD), molecular changes are observed not only in patients' neurons but also in peripheral cells, such as blood lymphocytes. These include changes in the level of oxidative stress markers, mitochondria impairment, and aberrant cell cycle regulation in AD blood lymphocytes. While the concepts of early causes of AD are currently highly controversial, these findings provide support for the cell cycle hypothesis of AD pathomechanism and emphasize the systemic nature of the disease. Moreover, because of difficulties in studying dynamic processes in the human brain, lymphocytes seem to be useful for readout of AD molecular mechanisms. In addition, lymphocytes as easily accessible human cells have potential diagnostic value. We summarize current perspectives for the development of new therapeutic strategies based on oxidative stress and cell cycle dysregulation in AD, and for diagnostic methodologies involving new markers in AD lymphocytes.
    Journal of Alzheimer's disease: JAD 03/2015; 46(2). DOI:10.3233/JAD-141977 · 4.15 Impact Factor
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    • "It is proposed that presenilin itself can function as an ER membrane calcium leak channel that maintains calcium homeostasis in the ER. Mutant presenilin may be impaired in this role, allowing ER stores to become overfilled and leading to increased calcium release (Honarnejad et al., 2013; Nelson et al., 2011, 2007; Tu et al., 2006). This hypothesis, while compelling, is still controversial (Shilling et al., 2012). "
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    European journal of pharmacology 12/2013; DOI:10.1016/j.ejphar.2013.11.012 · 2.68 Impact Factor
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    • "These authors discovered that PSH has a large hole that transverse the entire protein and is surrounded by transmembrane domains 2, 3, 5, and 7. These data are in good agreement with our mutagenesis mapping studies (Nelson et al., 2011). Moreover, these authors postulate that the hole is large enough to allow passage of the small ions (Li et al., 2013), suggesting that PSH may function as an ion channel. "
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