Presenilins function in ER calcium leak and Alzheimer's disease pathogenesis

Supnet, Charlene; Bezprozvanny, Ilya

doi:10.1016/j.ceca.2011.05.013

Cited by 86 publications

(58 citation statements)

References 91 publications

(162 reference statements)

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“…BLM recordings with recombinant presenilins were used to show their ability to support ER Ca 2+ leak and to show that most familial AD mutations in presenilins disrupt their leak function (Tu et al 2006; Nelson et al 2007). Obtained results provided strong support to the hypothesis that aberrant Ca 2+ signaling plays a role in AD (Bezprozvanny and Mattson 2008; Bezprozvanny 2009; Supnet and Bezprozvanny 2011). BLM recordings were used to confirm the recent discovery that the TPC2 ion channel functions as a NAADP-gated lysosomal Ca 2+ channel and to study regulation of this channel by lysosomal Ca 2+ and pH (Pitt et al 2010).…”

Section: Other Uses For Blm Methodssupporting

confidence: 68%

Bilayer Measurement of Endoplasmic Reticulum Ca²⁺ Channels

Bezprozvanny

2013

Cold Spring Harb Protoc

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Reconstitution of ion channels into planar lipid bilayers (also called black lipid membranes or BLM) is the most widely used method to conduct physiological studies of intracellular ion channels, including endoplasmic reticulum (ER) calcium (Ca2+) channels. The two main types of Ca2+ release channels in the ER membrane are ryanodine receptors (RyanRs) and inositol(1,4,5)-trisphosphate receptors (InsP3Rs). Use of the BLM reconstitution technique enabled the initial description of the functional properties of InsP3R and RyanR at the single-channel level more than 20 years ago. Since then, BLM reconstitution methods have been used to study physiological modulation and to perform structure–function analysis of these channels, and to study pathological changes in the function of InsP3R and RyanR in various disease states. The BLM technique has also been useful for studies of other intracellular Ca2+ channels, such as ER Ca2+ leak presenilin channels and NAADP-gated lysosomal Ca2+ channels encoded by TPC2. In this article, basic protocols used for BLM studies of ER Ca2+ channels are introduced.

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Section: Other Uses For Blm Methodssupporting

confidence: 68%

Bilayer Measurement of Endoplasmic Reticulum Ca²⁺ Channels

Bezprozvanny

2013

Cold Spring Harb Protoc

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“…PS has been implicated in the regulation of intracellular Ca 2+ homeostasis, but the precise site(s) of its action remains controversial (4). For example, it was proposed that PS holoproteins act as the passive ER calcium leak channel, based primarily on larger ionomycin-sensitive Ca 2+ pool in immortalized PS DKO mouse embryonic fibroblasts (MEFs) (9,30). However, using ER-targeted calcium probes, including Mag-Fura-2, another group failed to find increases in Ca 2+ stores in the ER using the same immortalized MEFs; rather, they found no difference in ER Ca 2+ dynamics between the immortalized PS DKO MEFs and the DKO MEFs retrovirally transfected to express wild-type PS1 (11).…”

Section: +mentioning

confidence: 99%

Presenilins regulate calcium homeostasis and presynaptic function via ryanodine receptors in hippocampal neurons

Yamaguchi

Lai

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

107

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Presenilin (PS) plays a central role in the pathogenesis of Alzheimer's disease, and loss of PS causes progressive memory impairment and age-related neurodegeneration in the mouse cerebral cortex. In hippocampal neurons, PS is essential for neurotransmitter release, NMDA receptor-mediated responses, and long-term potentiation. PS is also involved in the regulation of calcium homeostasis, although the precise site of its action is less clear. Here we investigate the mechanism by which PS regulates synaptic function and calcium homeostasis using acute hippocampal slices from PS conditional knockout mice and primary cultured postnatal hippocampal neurons, in which PS is inducibly inactivated. Using two different calcium probes, Fura-2 and Mag-Fura-2, we found that inactivation of PS in primary hippocampal neurons does not affect calcium concentration in the endoplasmic reticulum. Rather, in the absence of PS, levels of ryanodine receptor (RyR) are reduced in the hippocampus, measured by Western analysis and radioligand binding assay, although the mRNA expression is unaffected. RyRmediated function is also impaired, as indicated by reduced RyR agonist-induced calcium release from the ER and RyR-mediated synaptic responses in the absence of PS. Furthermore, knockdown of RyR expression in wild-type hippocampal neurons by two independent shRNAs to levels comparable with the RyR protein reduction in PS-deficient hippocampal neurons mimics the defects exhibited in calcium homeostasis and presynaptic function. Collectively, our findings show that PS regulates calcium homeostasis and synaptic function via RyR and suggest that disruption of intracellular calcium homeostasis may be an early pathogenic event leading to presynaptic dysfunction in Alzheimer's disease.ER calcium | caffeine M utations in the presenilin (PS) genes account for ∼90% of causative mutations in familial Alzheimer's disease (AD), highlighting the importance of PS in the pathogenesis of AD. We previously reported that presenilins play essential roles in the regulation of long-term potentiation, short-term plasticity and neurotransmitter release (1-4). Interestingly, presynaptic defects caused by loss of presynaptic PS can be mimicked by depletion of calcium in the endoplasmic reticulum (ER), suggesting that disrupted intracellular calcium homeostasis may underlie these presynaptic defects (2). Although large numbers of reports have indicated an involvement of PS in the regulation of intracellular calcium homeostasis, the precise site of its action is less clear (4, 5).The ER is a major source of intracellular calcium and is present in both axonal and dendritic compartments (6). Cytosolic calcium is pumped into the ER by sarco-ER calcium ATPase (SERCA), and calcium release from the ER into the cytosol can be mediated through either the ryanodine receptor (RyR) or the inositol 1,4,5 trisphosphate receptor (IP 3 R). Blockade of the RyR but not the IP 3 R mimics and occludes the presynaptic defects in hippocampal slices of CA3-PS conditional double knockout ...

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“…75-78 As shown in figure 1, mutations in presenilin-1 (PS1) and presenilin-2 (PS2) associated with familial AD (FAD), significantly enhance the expression and activation of RYRs, as well as the activation of InsP 3 Rs, resulting in excessive Ca 2+ release from the ER and abnormal cytosolic Ca 2+ concentration [Ca 2+ ] c elevation. 50,79-81 On the other hand, the ApoE4 gene, a widely accepted genetic risk factor for sporadic AD, has been shown to disrupt intracellular Ca 2+ homeostasis by abnormally increasing NMDA receptor activation, which may result in excessive Ca 2+ influx, elevation of [Ca 2+ ] c , and Ca 2+ -induced Ca 2+ release (CICR) from the ER via RYRs and/or IP 3 Rs.…”

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confidence: 99%

Dantrolene, A Treatment for Alzheimer Disease?

Wei

2015

Alzheimer Disease &Amp; Associated Disorders

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Alzheimer's disease (AD) is a fatal progressive disease and the most common form of dementia without effective treatments. Previous studies support that the disruption of endoplasmic reticulum (ER) Ca2+ via overactivation of Ryanodine receptors (RYRs) plays an important role in the pathogenesis of AD. Normalization of intracellular Ca2+ homeostasis could be an effective strategy for AD therapies. Dantrolene, an antagonist of RYRs and an FDA approved drug for clinical treatment of malignant hyperthermia and muscle spasms, exhibits neuroprotective effects in multiple models of neurodegenerative disorders. Recent preclinical studies consistently support the therapeutic effects of dantrolene in various types of AD animal models and were summarized in the current review.

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Presenilins function in ER calcium leak and Alzheimer's disease pathogenesis

Cited by 86 publications

References 91 publications

Bilayer Measurement of Endoplasmic Reticulum Ca²⁺ Channels

Bilayer Measurement of Endoplasmic Reticulum Ca²⁺ Channels

Presenilins regulate calcium homeostasis and presynaptic function via ryanodine receptors in hippocampal neurons

Dantrolene, A Treatment for Alzheimer Disease?

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Presenilins function in ER calcium leak and Alzheimer's disease pathogenesis

Cited by 86 publications

References 91 publications

Bilayer Measurement of Endoplasmic Reticulum Ca2+ Channels

Bilayer Measurement of Endoplasmic Reticulum Ca2+ Channels

Presenilins regulate calcium homeostasis and presynaptic function via ryanodine receptors in hippocampal neurons

Dantrolene, A Treatment for Alzheimer Disease?

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Bilayer Measurement of Endoplasmic Reticulum Ca²⁺ Channels

Bilayer Measurement of Endoplasmic Reticulum Ca²⁺ Channels