Presenilins as endoplasmic reticulum calcium leak channels and Alzheimer’s disease pathogenesis

Supnet, Charlene; Bezprozvanny, Ilya

doi:10.1007/s11427-011-4201-y

Cited by 16 publications

(6 citation statements)

References 91 publications

(160 reference statements)

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“…An Aβ induced activation of ryanodine receptors (RyR) has been reported for RyR1 reconstituted in planar lipid bilayers [149] and Aβ42 has been shown to increase the expression of RyR3 [150]. Interestingly, several studies have also linked familial PS mutations, increasing the ratio of Aβ42 to Aβ40 peptides, with elevated Ca 2+ release out of the ER [151][152][153][154].…”

Section: Cholinergic Dysfunctionmentioning

confidence: 99%

Recent Understanding of the Molecular Mechanisms of Alzheimer?s Disease

Grimm¹,

Hartmann²

2011

J Addict Res Ther

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Alzheimer's disease (AD) is the most common form of dementia in the elderly and is characterized in patients by an inexorably progression, causing problems with memory, thinking and behaviour. Currently 25 million people worldwide are estimated to be affected by AD with the highest number in North America, Latin America, Western Europe, China and the western pacific [1]. Epidemiological studies predict that the incidence of AD will increase due to increasing life expectancy to 42.3 million in 2020 and 81.1 million in 2040 [1,2], emphasizing AD as a major public health concern.The two main histopathological hallmarks of AD are extracellular amyloid plaques and intracellular neurofibrillary tangles in vulnerable brain regions like hippocampus and cortex [3]. The amyloid plaques, also called senile plaques, are mainly composed of amyloid-beta peptides (Aβ), most of which are 38 to 43 amino acids long [4]. Aβ peptides are generated by sequential processing of the amyloid precursor protein (APP), a large type-I transmembrane protein [5] that belongs to an evolutionary conserved protein family including beside APP, the APP-like protein 1 (APLP1) and 2 (APLP2) in mammals [6,7] with the Aβ domain to be unique to APP [8]. The second characteristic pathological hallmark of AD, the intracellular neurofibrillary tangles, consist of an abnormally phosphorylated form of the microtubule-associated protein tau [9]. In contrast to amyloid plaques, which accumulate extracellularly in the brains of AD affected individuals and have been long believed to cause neuronal damage and cell death, neurofibrillary tangles are found inside neurons and their branching points like axons and dendrites [10,11]. Proteolytic Processing of APP Amyloidogenic APP processingProteolytic processing of APP leading to Aβ peptides is a ubiquitous cellular process involving β-and γ-secretase activity (Figure 1). The first step in Aβ production is APP cleavage by β-secretase, generating the N-terminus of Aβ. BACE 1 (β-site APP cleaving enzyme, also called Asp2 or memapsin2) was identified as the major β-secretase, a membrane-bound protease that belongs to the pepsin family of aspartyl proteases [12][13][14]. Aβ generation is abolished in cultures of BACE1-deficient embryonic cortical neurons [15] and in BACE1 knock-out mice [16,17]. Whereas Luo and Roberds et al. [16,17] reported a normal phenotype of BACE1-deficient mice, more recent studies found severe phenotypic abnormalities in BACE1 knock-out mice [18], challenging BACE1 as safe drug target for AD. Furthermore, additional BACE1 substrates have been reported, suggesting a variety of BACE1 physiological functions. Identified substrates include proteins with important neuronal function, like the β2-subunit of the voltage-gated sodium channel (Navβ2) [19,20], important for normal action potential regulation and neuronal excitability, and neuregulin-1 [21,22], as ligand for members of the ErbB family of receptor-tyrosine kinases, involved in synapse formation, myelination of central and peripheral axon...

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Section: Cholinergic Dysfunctionmentioning

confidence: 99%

Recent Understanding of the Molecular Mechanisms of Alzheimer?s Disease

Grimm¹,

Hartmann²

2011

J Addict Res Ther

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“…Decreases in the ER Ca 2 + concentration trigger the unfolded protein response and several Ca 2 + -binding proteins residing within the lumen of the ER, notably the highly expressed chaperones calreticulin and BiP/Grp78, help maintain high resting Ca 2 + levels by sequestering Ca 2 + ions (34). Ca 2 + constitutively leaks out of the ER via Sec61 translocon complexes (60,103) and possibly presenilins (187), although the latter is controversial is extruded from cells by the plasma membrane calcium ATPase (PMCA) and sodium-calcium exchanger (NCX), and sequestered into the endoplasmic reticulum (ER) by sarcoendoplasmic reticulum calcium ATPase (SERCA) pumps. SOCE is initiated when Ca 2 + is released from the ER, such as upon activation of inositol 1,4,5 triphosphate receptors (IP 3 R) or ryanodine receptors (RyR).…”

Section: E Levations In Intracellular Camentioning

confidence: 99%

Redox Regulation of Store-Operated Ca²⁺Entry

Nunes

Demaurex

2014

Antioxidants & Redox Signaling

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Significance: Store-operated Ca 2+ entry (SOCE) is a ubiquitous Ca 2+ signaling mechanism triggered by Ca 2+ depletion of the endoplasmic reticulum (ER) and by a variety of cellular stresses. Reactive oxygen species (ROS) are often concomitantly produced in response to these stresses, however, the relationship between redox signaling and SOCE is not completely understood. Various cardiovascular, neurological, and immune diseases are associated with alterations in both Ca 2+ signaling and ROS production, and thus understanding this relationship has therapeutic implications. Recent Advances: Several reactive cysteine modifications in stromal interaction molecule (STIM) and Orai proteins comprising the core SOCE machinery were recently shown to modulate SOCE in a redox-dependent manner. Moreover, STIM1 and Orai1 expression levels may reciprocally regulate and be affected by responses to oxidative stress. ER proteins involved in oxidative protein folding have gained increased recognition as important sources of ROS, and the recent discovery of their accumulation in contact sites between the ER and mitochondria provides a further link between ROS production and intracellular Ca 2+ handling. Critical Issues and Future Directions: Future research should aim to establish the complete set of SOCE controlling molecules, to determine their redox-sensitive residues, and to understand how intracellular Ca 2+ stores dynamically respond to different types of stress. Mapping the precise nature and functional consequence of key redox-sensitive components of the pre-and post-translational control of SOCE machinery and of proteins regulating ER calcium content will be pivotal in advancing our understanding of the complex crosstalk between redox and Ca 2+ signaling. Antioxid. Redox Signal. 21, 915-932.

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“…The mechanism underlying these unique clinical and pathological phenotypes is unknown. It is well established that Ca 2+ release from intracellular stores is increased in both sporadic and familial AD [171-173], and thus it is proposed that the disturbed Ca 2+ regulation in FAD is correlated with CWP [174,175]. Over 20 PS1 mutations have been analyzed and though all PS1 mutations show increased Aβ42/40 ratio, their effects on calcium signaling are various.…”

Section: Presenilins and Calcium Regulationmentioning

confidence: 99%

Biological function of Presenilin and its role in AD pathogenesis

Zhang

Cai

et al. 2013

Transl Neurodegener

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Presenilins (PSs) are the catalytic core of γ-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 γ-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 γ-secretase dependent and γ-secretase independent ones. The γ-secretase dependent functions of presenilins are exemplified by the sequential cleavages in the processing of APP and Notch; the γ-secretase independent functions of presenilins include stabilizing β-catenin in Wnt signaling pathway, regulating calcium homeostasis and their interaction with synaptic transmission.

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Presenilins as endoplasmic reticulum calcium leak channels and Alzheimer’s disease pathogenesis

Cited by 16 publications

References 91 publications

Recent Understanding of the Molecular Mechanisms of Alzheimer?s Disease

Recent Understanding of the Molecular Mechanisms of Alzheimer?s Disease

Redox Regulation of Store-Operated Ca²⁺Entry

Biological function of Presenilin and its role in AD pathogenesis

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Presenilins as endoplasmic reticulum calcium leak channels and Alzheimer’s disease pathogenesis

Cited by 16 publications

References 91 publications

Recent Understanding of the Molecular Mechanisms of Alzheimer?s Disease

Recent Understanding of the Molecular Mechanisms of Alzheimer?s Disease

Redox Regulation of Store-Operated Ca2+Entry

Biological function of Presenilin and its role in AD pathogenesis

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Redox Regulation of Store-Operated Ca²⁺Entry