Role of Presenilins in Neuronal Calcium Homeostasis

Department of Physiology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390, USA.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 06/2010; 30(25):8566-80. DOI: 10.1523/JNEUROSCI.1554-10.2010
Source: PubMed


Alzheimer's disease (AD) is a progressive and irreversible neurodegenerative disorder. Familial AD (FAD) mutations in presenilins have been linked to calcium (Ca(2+)) signaling abnormalities. To explain these results, we previously proposed that presenilins function as endoplasmic reticulum (ER) passive Ca(2+) leak channels. To directly investigate the role of presenilins in neuronal ER Ca(2+) homeostasis, we here performed a series of Ca(2+) imaging experiments with primary neuronal cultures from conditional presenilin double-knock-out mice (PS1(dTAG/dTAG), PS2(-/-)) and from triple-transgenic AD mice (KI-PS1(M146V), Thy1-APP(KM670/671NL), Thy1-tau(P301L)). Obtained results provided additional support to the hypothesis that presenilins function as ER Ca(2+) leak channels in neurons. Interestingly, we discovered that presenilins play a major role in ER Ca(2+) leak function in hippocampal but not in striatal neurons. We further discovered that, in hippocampal neurons, loss of presenilin-mediated ER Ca(2+) leak function was compensated by an increase in expression and function of ryanodine receptors (RyanRs). Long-term feeding of the RyanR inhibitor dantrolene to amyloid precursor protein-presenilin-1 mice (Thy1-APP(KM670/671NL), Thy1-PS1(L166P)) resulted in an increased amyloid load, loss of synaptic markers, and neuronal atrophy in hippocampal and cortical regions. These results indicate that disruption of ER Ca(2+) leak function of presenilins may play an important role in AD pathogenesis.

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    • "Furthermore, PS1 FAD M146V mutant knock-in hippocampal cells showed reduced synaptic plasticity and defects in long-term potentiation (LTP), which can be rescued by inhibition of the RyR [99]. Conditional knockout of presenilins or expression of the PS1 FAD M146V mutant in mouse hippocampal cells has also been shown to increase ER Ca 2+ levels and enhance susceptibility to induced Ca 2+ release [100]. These cells also showed an increase in ER RyR levels, which the authors suggest, maybe a result of the decreased presenilin leak channel function, leading to the increased ER Ca 2+ levels and thus a need for an increase in ER Ca 2+ channel expression. "
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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.
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    • "Initially characterized as a protease responsible for the cleavage of amyloid precursor protein (APP) and the generation of amyloid-b peptides, the c-secretase protease is now known to be responsible for the cleavage of numerous type I transmembrane proteins associated with several developmental and cellular processes, including the Notch receptor, ErbB4, Cadherins, Insulin-like growth factor receptor (IGFR1) [21] and the interleukin-1 receptors, IL-1RI [22,23] and IL-1RII [24]. In addition to the well-researched role of presenilins as the catalytic core of the c-secretase protease, the involvement of presenilin holoproteins in the regulation of intracellular calcium homeostasis has become a focus of presenilin and Alzheimer's disease research [25] [26] [27] [28]. Critical to the complexity of presenilin-associated activities, PS1 and PS2 are differentially controlled by post-translational modifications including endoproteolysis, caspase cleavage, phosphorylation and ubiquitination [29]. "
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    • "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). "
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