International Journal of Molecular Sciences

Editorial

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3 pages, 191 KiB

Open AccessEditorial

The Eighth ECS Workshop on “Calcium Signaling in Aging and Neurodegenerative Diseases”

by Jan B. Parys, Cláudia F. Pereira and Carlos Villalobos

Int. J. Mol. Sci. 2019, 20(24), 6263; https://doi.org/10.3390/ijms20246263 - 12 Dec 2019

Cited by 2 | Viewed by 2436

Abstract

The European Calcium Society (ECS) is very glad to present the realization of a special issue of the International Journal of Molecular Sciences (IJMS) related to the eighth ECS workshop organized this year around the theme of “Calcium Signaling in Aging and Neurodegenerative [...] Read more.

The European Calcium Society (ECS) is very glad to present the realization of a special issue of the International Journal of Molecular Sciences (IJMS) related to the eighth ECS workshop organized this year around the theme of “Calcium Signaling in Aging and Neurodegenerative Diseases” [...] Full article

(This article belongs to the Special Issue 8th ECS Workshop 'Calcium Signaling in Aging and Neurodegenerative Diseases')

Research

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22 pages, 4402 KiB

Open AccessArticle

Calcium Modulation, Anti-Oxidant and Anti-Inflammatory Effect of Skin Allergens Targeting the Nrf2 Signaling Pathway in Alzheimer’s Disease Cellular Models

by Ana Silva, Marta Pereira, Mylène A. Carrascal, Gonçalo Brites, Bruno Neves, Patrícia Moreira, Rosa Resende, Maria Manuel Silva, Armanda E. Santos, Cláudia Pereira and Maria Teresa Cruz

Int. J. Mol. Sci. 2020, 21(20), 7791; https://doi.org/10.3390/ijms21207791 - 21 Oct 2020

Cited by 6 | Viewed by 3669

Abstract

Experimental evidence highlights nuclear factor (erythroid-derived 2)-like 2 (Nrf2) as a molecular target in Alzheimer’s disease (AD). The well-known effect of electrophilic cysteine-reactive skin allergens on Nrf2-activation led to the hypothesis that these compounds could have a therapeutic role in AD. This was [...] Read more.

Experimental evidence highlights nuclear factor (erythroid-derived 2)-like 2 (Nrf2) as a molecular target in Alzheimer’s disease (AD). The well-known effect of electrophilic cysteine-reactive skin allergens on Nrf2-activation led to the hypothesis that these compounds could have a therapeutic role in AD. This was further supported by the neuroprotective activity of the skin allergen dimethyl fumarate (DMF), demonstrated in in vivo models of neurodegenerative diseases. We evaluated the effect of the cysteine-reactive allergens 1,4-phenylenediamine (PPD) and methyl heptine carbonate (MHC) on (1) neuronal redox imbalance and calcium dyshomeostasis using N2a wild-type (N2a-wt) and human APP-overexpressing neuronal cells (wild-type, N2a-APPwt) and (2) on neuroinflammation, using microglia BV-2 cells exposed to LPS (lipopolysaccharide). Phthalic anhydride (PA, mainly lysine-reactive), was used as a negative control. DMF, PPD and MHC increased Hmox1 gene and HMOX1 protein levels in N2a-APPwt cells suggesting Nrf2-dependent antioxidant activity. MHC, but also PA, rescued N2a-APPwt mitochondrial membrane potential and calcium levels in a Nrf2-independent pathway. All the chemicals showed anti-inflammatory activity by decreasing iNOS protein in microglia. This work highlights the potential neuroprotective and anti-inflammatory role of the selected skin allergens in in vitro models of AD, and supports further studies envisaging the validation of the results using in vivo AD models. Full article

(This article belongs to the Special Issue 8th ECS Workshop 'Calcium Signaling in Aging and Neurodegenerative Diseases')

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13 pages, 1528 KiB

Open AccessArticle

Role of the TRPC1 Channel in Hippocampal Long-Term Depression and in Spatial Memory Extinction

by Xavier Yerna, Olivier Schakman, Ikram Ratbi, Anna Kreis, Sophie Lepannetier, Marie de Clippele, Younès Achouri, Nicolas Tajeddine, Fadel Tissir, Roberta Gualdani and Philippe Gailly

Int. J. Mol. Sci. 2020, 21(5), 1712; https://doi.org/10.3390/ijms21051712 - 3 Mar 2020

Cited by 15 | Viewed by 3997

Abstract

Group I metabotropic glutamate receptors (mGluR) are involved in various forms of synaptic plasticity that are believed to underlie declarative memory. We previously showed that mGluR5 specifically activates channels containing TRPC1, an isoform of the canonical family of Transient Receptor Potential channels highly [...] Read more.

Group I metabotropic glutamate receptors (mGluR) are involved in various forms of synaptic plasticity that are believed to underlie declarative memory. We previously showed that mGluR5 specifically activates channels containing TRPC1, an isoform of the canonical family of Transient Receptor Potential channels highly expressed in the CA1-3 regions of the hippocampus. Using a tamoxifen-inducible conditional knockout model, we show here that the acute deletion of the Trpc1 gene alters the extinction of spatial reference memory. mGluR-induced long-term depression, which is partially responsible for memory extinction, was impaired in these mice. Similar results were obtained in vitro and in vivo by inhibiting the channel by its most specific inhibitor, Pico145. Among the numerous known postsynaptic pathways activated by type I mGluR, we observed that the deletion of Trpc1 impaired the activation of ERK1/2 and the subsequent expression of Arc, an immediate early gene that plays a key role in AMPA receptors endocytosis and subsequent long-term depression. Full article

(This article belongs to the Special Issue 8th ECS Workshop 'Calcium Signaling in Aging and Neurodegenerative Diseases')

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13 pages, 1625 KiB

Open AccessArticle

Human-Induced Neurons from Presenilin 1 Mutant Patients Model Aspects of Alzheimer’s Disease Pathology

by Sean Schrank, John McDaid, Clark A. Briggs, Sarah Mustaly-Kalimi, Deanna Brinks, Aiden Houcek, Oded Singer, Virginie Bottero, Robert A. Marr and Grace E. Stutzmann

Int. J. Mol. Sci. 2020, 21(3), 1030; https://doi.org/10.3390/ijms21031030 - 4 Feb 2020

Cited by 10 | Viewed by 4722

Abstract

Traditional approaches to studying Alzheimer’s disease (AD) using mouse models and cell lines have advanced our understanding of AD pathogenesis. However, with the growing divide between model systems and clinical therapeutic outcomes, the limitations of these approaches are increasingly apparent. Thus, to generate [...] Read more.

Traditional approaches to studying Alzheimer’s disease (AD) using mouse models and cell lines have advanced our understanding of AD pathogenesis. However, with the growing divide between model systems and clinical therapeutic outcomes, the limitations of these approaches are increasingly apparent. Thus, to generate more clinically relevant systems that capture pathological cascades within human neurons, we generated human-induced neurons (HiNs) from AD and non-AD individuals to model cell autonomous disease properties. We selected an AD patient population expressing mutations in presenilin 1 (mPS1), which is linked to increased amyloid production, tau pathology, and calcium signaling abnormalities, among other features. While these AD components are detailed in model systems, they have yet to be collectively identified in human neurons. Thus, we conducted molecular, immune-based, electrophysiological, and calcium imaging studies to establish patterns of cellular pathology in this patient population. We found that mPS1 HiNs generate increased Aβ₄₂ and hyperphosphorylated tau species relative to non-AD controls, and exaggerated ER calcium responses that are normalized with ryanodine receptor (RyR) negative allosteric modulators. The inflammasome product, interleukin-18 (IL-18), also increased PS1 expression. This work highlights the potential for HiNs to model AD pathology and validates their role in defining cellular pathogenesis and their utility for therapeutic screening. Full article

(This article belongs to the Special Issue 8th ECS Workshop 'Calcium Signaling in Aging and Neurodegenerative Diseases')

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15 pages, 2938 KiB

Open AccessArticle

Transgenic Mice Overexpressing Human STIM2 and ORAI1 in Neurons Exhibit Changes in Behavior and Calcium Homeostasis but Show No Signs of Neurodegeneration

by Lukasz Majewski, Filip Maciąg, Pawel M. Boguszewski and Jacek Kuznicki

Int. J. Mol. Sci. 2020, 21(3), 842; https://doi.org/10.3390/ijms21030842 - 28 Jan 2020

Cited by 8 | Viewed by 3674

Abstract

The maintenance of proper cytosolic Ca²⁺ level is crucial for neuronal survival, and dysregulation of Ca²⁺ homeostasis is found in a variety of neurological disorders, including Alzheimer’s disease. According to the “Ca²⁺ hypothesis of aging”, Ca²⁺ disturbances precede the [...] Read more.

The maintenance of proper cytosolic Ca²⁺ level is crucial for neuronal survival, and dysregulation of Ca²⁺ homeostasis is found in a variety of neurological disorders, including Alzheimer’s disease. According to the “Ca²⁺ hypothesis of aging”, Ca²⁺ disturbances precede the onset of AD symptoms and lead to neurodegeneration. STIM and ORAI proteins are involved in neuronal physiological and pathological processes as essential components of the store-operated Ca²⁺ entry. Our previous data suggested that overexpression of STIM2 and ORAI1 might increase basal neuronal cytosolic Ca²⁺ level. We generated double transgenic mice overexpressing these two genes in neurons, expecting that the increased basal Ca²⁺ concentration will lead to premature neurodegeneration. We observed changes in Ca²⁺ homeostasis and electrophysiological properties in acute brain slices of STIM2/ORAI1 neurons. However, we did not observe any augmentation of neurodegenerative processes, as tested by Fluoro-Jade^® C staining and assessment of amyloidogenesis. The battery of behavioral tests did not show any signs of accelerated aging. We conclude that changes of calcium homeostasis induced by overexpression of STIM2 and ORAI1 had no substantial adverse effects on neurons and did not lead to early neurodegeneration. Full article

(This article belongs to the Special Issue 8th ECS Workshop 'Calcium Signaling in Aging and Neurodegenerative Diseases')

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13 pages, 7566 KiB

Open AccessArticle

Tonic Activation of Extrasynaptic NMDA Receptors Decreases Intrinsic Excitability and Promotes Bistability in a Model of Neuronal Activity

by David Gall and Geneviève Dupont

Int. J. Mol. Sci. 2020, 21(1), 206; https://doi.org/10.3390/ijms21010206 - 27 Dec 2019

Cited by 7 | Viewed by 3735

Abstract

NMDA receptors (NMDA-R) typically contribute to excitatory synaptic transmission in the central nervous system. While calcium influx through NMDA-R plays a critical role in synaptic plasticity, experimental evidence indicates that NMDAR-mediated calcium influx also modifies neuronal excitability through the activation of calcium-activated potassium [...] Read more.

NMDA receptors (NMDA-R) typically contribute to excitatory synaptic transmission in the central nervous system. While calcium influx through NMDA-R plays a critical role in synaptic plasticity, experimental evidence indicates that NMDAR-mediated calcium influx also modifies neuronal excitability through the activation of calcium-activated potassium channels. This mechanism has not yet been studied theoretically. Our theoretical model provides a simple description of neuronal electrical activity that takes into account the tonic activity of extrasynaptic NMDA receptors and a cytosolic calcium compartment. We show that calcium influx mediated by the tonic activity of NMDA-R can be coupled directly to the activation of calcium-activated potassium channels, resulting in an overall inhibitory effect on neuronal excitability. Furthermore, the presence of tonic NMDA-R activity promotes bistability in electrical activity by dramatically increasing the stimulus interval where both a stable steady state and repetitive firing can coexist. These results could provide an intrinsic mechanism for the constitution of memory traces in neuronal circuits. They also shed light on the way by which

β

-amyloids can alter neuronal activity when interfering with NMDA-R in Alzheimer’s disease and cerebral ischemia. Full article

(This article belongs to the Special Issue 8th ECS Workshop 'Calcium Signaling in Aging and Neurodegenerative Diseases')

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25 pages, 11962 KiB

Open AccessArticle

Examining Cardiomyocyte Dysfunction Using Acute Chemical Induction of an Ageing Phenotype

by Said Masoud, Fraser McDonald, Dirk Bister, Claire Kotecki, Martin D. Bootman and Katja Rietdorf

Int. J. Mol. Sci. 2020, 21(1), 197; https://doi.org/10.3390/ijms21010197 - 27 Dec 2019

Cited by 4 | Viewed by 3724

Abstract

Much effort is focussed on understanding the structural and functional changes in the heart that underlie age-dependent deterioration of cardiac performance. Longitudinal studies, using aged animals, have pinpointed changes occurring to the contractile myocytes within the heart. However, whilst longitudinal studies are important, [...] Read more.

Much effort is focussed on understanding the structural and functional changes in the heart that underlie age-dependent deterioration of cardiac performance. Longitudinal studies, using aged animals, have pinpointed changes occurring to the contractile myocytes within the heart. However, whilst longitudinal studies are important, other experimental approaches are being advanced that can recapitulate the phenotypic changes seen during ageing. This study investigated the induction of an ageing cardiomyocyte phenotypic change by incubation of cells with hydroxyurea for several days ex vivo. Hydroxyurea incubation has been demonstrated to phenocopy age- and senescence-induced changes in neurons, but its utility for ageing studies with cardiac cells has not been examined. Incubation of neonatal rat ventricular myocytes with hydroxyurea for up to 7 days replicated specific aspects of cardiac ageing including reduced systolic calcium responses, increased alternans and a lesser ability of the cells to follow electrical pacing. Additional functional and structural changes were observed within the myocytes that pointed to ageing-like remodelling, including lipofuscin granule accumulation, reduced mitochondrial membrane potential, increased production of reactive oxygen species, and altered ultrastructure, such as mitochondria with disrupted cristae and disorganised myofibres. These data highlight the utility of alternative approaches for exploring cellular ageing whilst avoiding the costs and co-morbid factors that can affect longitudinal studies. Full article

(This article belongs to the Special Issue 8th ECS Workshop 'Calcium Signaling in Aging and Neurodegenerative Diseases')

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Review

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9 pages, 951 KiB

Open AccessReview

Disruption of Exocytosis in Sympathoadrenal Chromaffin Cells from Mouse Models of Neurodegenerative Diseases

by Antonio M. G. de Diego, Diana Ortega-Cruz and Antonio G. García

Int. J. Mol. Sci. 2020, 21(6), 1946; https://doi.org/10.3390/ijms21061946 - 12 Mar 2020

Cited by 8 | Viewed by 3806

Abstract

Synaptic disruption and altered neurotransmitter release occurs in the brains of patients and in murine models of neurodegenerative diseases (NDDs). During the last few years, evidence has accumulated suggesting that the sympathoadrenal axis is also affected as disease progresses. Here, we review a [...] Read more.

Synaptic disruption and altered neurotransmitter release occurs in the brains of patients and in murine models of neurodegenerative diseases (NDDs). During the last few years, evidence has accumulated suggesting that the sympathoadrenal axis is also affected as disease progresses. Here, we review a few studies done in adrenal medullary chromaffin cells (CCs), that are considered as the amplifying arm of the sympathetic nervous system; the sudden fast exocytotic release of their catecholamines—stored in noradrenergic and adrenergic cells—plays a fundamental role in the stress fight-or-flight response. Bulk exocytosis and the fine kinetics of single-vesicle exocytotic events have been studied in mouse models carrying a mutation linked to NDDs. For instance, in R6/1 mouse models of Huntington’s disease (HD), mutated huntingtin is overexpressed in CCs; this causes decreased quantal secretion, smaller quantal size and faster kinetics of the exocytotic fusion pore, pore expansion, and closure. This was accompanied by decreased sodium current, decreased acetylcholine-evoked action potentials, and attenuated [Ca²⁺]c transients with faster Ca²⁺ clearance. In the SOD1^G93A mouse model of amyotrophic lateral sclerosis (ALS), CCs exhibited secretory single-vesicle spikes with a slower release rate but higher exocytosis. Finally, in the APP/PS1 mouse model of Alzheimer’s disease (AD), the stabilization, expansion, and closure of the fusion pore was faster, but the secretion was attenuated. Additionally, α-synuclein that is associated with Parkinson’s disease (PD) decreases exocytosis and promotes fusion pore dilation in adrenal CCs. Furthermore, Huntington-associated protein 1 (HAP1) interacts with the huntingtin that, when mutated, causes Huntington’s disease (HD); HAP1 reduces full fusion exocytosis by affecting vesicle docking and controlling fusion pore stabilization. The alterations described here are consistent with the hypothesis that central alterations undergone in various NDDs are also manifested at the peripheral sympathoadrenal axis to impair the stress fight-or-flight response in patients suffering from those diseases. Such alterations may occur: (i) primarily by the expression of mutated disease proteins in CCs; (ii) secondarily to stress adaptation imposed by disease progression and the limitations of patient autonomy. Full article

(This article belongs to the Special Issue 8th ECS Workshop 'Calcium Signaling in Aging and Neurodegenerative Diseases')

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8 pages, 825 KiB

Open AccessReview

Neuronal Activity and Its Role in Controlling Antioxidant Genes

by Jing Qiu, Owen Dando, James A. Febery, Jill H. Fowler, Siddharthan Chandran and Giles E. Hardingham

Int. J. Mol. Sci. 2020, 21(6), 1933; https://doi.org/10.3390/ijms21061933 - 12 Mar 2020

Cited by 11 | Viewed by 3364

Abstract

Forebrain neurons have relatively weak intrinsic antioxidant defenses compared to astrocytes, in part due to hypo-expression of Nrf2, an oxidative stress-induced master regulator of antioxidant and detoxification genes. Nevertheless, neurons do possess the capacity to auto-regulate their antioxidant defenses in response to electrical [...] Read more.

Forebrain neurons have relatively weak intrinsic antioxidant defenses compared to astrocytes, in part due to hypo-expression of Nrf2, an oxidative stress-induced master regulator of antioxidant and detoxification genes. Nevertheless, neurons do possess the capacity to auto-regulate their antioxidant defenses in response to electrical activity. Activity-dependent Ca²⁺ signals control the expression of several antioxidant genes, boosting redox buffering capacity, thus meeting the elevated antioxidant requirements associated with metabolically expensive electrical activity. These genes include examples which are reported Nrf2 target genes and yet are induced in a Nrf2-independent manner. Here we discuss the implications for Nrf2 hypofunction in neurons and the mechanisms underlying the Nrf2-independent induction of antioxidant genes by electrical activity. A significant proportion of Nrf2 target genes, defined as those genes controlled by Nrf2 in astrocytes, are regulated by activity-dependent Ca²⁺ signals in human stem cell-derived neurons. We propose that neurons interpret Ca²⁺ signals in a similar way to other cell types sense redox imbalance, to broadly induce antioxidant and detoxification genes. Full article

(This article belongs to the Special Issue 8th ECS Workshop 'Calcium Signaling in Aging and Neurodegenerative Diseases')

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17 pages, 1420 KiB

Open AccessReview

PINK1/Parkin Mediated Mitophagy, Ca²⁺ Signalling, and ER–Mitochondria Contacts in Parkinson’s Disease

by Lucia Barazzuol, Flavia Giamogante, Marisa Brini and Tito Calì

Int. J. Mol. Sci. 2020, 21(5), 1772; https://doi.org/10.3390/ijms21051772 - 5 Mar 2020

Cited by 134 | Viewed by 13389

Abstract

Endoplasmic reticulum (ER)–mitochondria contact sites are critical structures for cellular function. They are implicated in a plethora of cellular processes, including Ca²⁺ signalling and mitophagy, the selective degradation of damaged mitochondria. Phosphatase and tensin homolog (PTEN)-induced kinase (PINK) and Parkin proteins, whose [...] Read more.

Endoplasmic reticulum (ER)–mitochondria contact sites are critical structures for cellular function. They are implicated in a plethora of cellular processes, including Ca²⁺ signalling and mitophagy, the selective degradation of damaged mitochondria. Phosphatase and tensin homolog (PTEN)-induced kinase (PINK) and Parkin proteins, whose mutations are associated with familial forms of Parkinson’s disease, are two of the best characterized mitophagy players. They accumulate at ER–mitochondria contact sites and modulate organelles crosstalk. Alterations in ER–mitochondria tethering are a common hallmark of many neurodegenerative diseases including Parkinson’s disease. Here, we summarize the current knowledge on the involvement of PINK1 and Parkin at the ER–mitochondria contact sites and their role in the modulation of Ca²⁺ signalling and mitophagy. Full article

(This article belongs to the Special Issue 8th ECS Workshop 'Calcium Signaling in Aging and Neurodegenerative Diseases')

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12 pages, 703 KiB

Open AccessReview

Remodeling of Intracellular Ca²⁺ Homeostasis in Rat Hippocampal Neurons Aged In Vitro

by Maria Calvo-Rodriguez, Elena Hernando-Pérez, Sara López-Vázquez, Javier Núñez, Carlos Villalobos and Lucía Núñez

Int. J. Mol. Sci. 2020, 21(4), 1549; https://doi.org/10.3390/ijms21041549 - 24 Feb 2020

Cited by 32 | Viewed by 4683

Abstract

Aging is often associated with a cognitive decline and a susceptibility to neuronal damage. It is also the most important risk factor for neurodegenerative disorders, particularly Alzheimer’s disease (AD). AD is related to an excess of neurotoxic oligomers of amyloid β peptide (Aβo); [...] Read more.

Aging is often associated with a cognitive decline and a susceptibility to neuronal damage. It is also the most important risk factor for neurodegenerative disorders, particularly Alzheimer’s disease (AD). AD is related to an excess of neurotoxic oligomers of amyloid β peptide (Aβo); however, the molecular mechanisms are still highly controversial. Intracellular Ca²⁺ homeostasis plays an important role in the control of neuronal activity, including neurotransmitter release, synaptic plasticity, and memory storage, as well as neuron cell death. Recent evidence indicates that long-term cultures of rat hippocampal neurons, resembling aged neurons, undergo cell death after treatment with Aβo, whereas short-term cultures, resembling young neurons, do not. These in vitro changes are associated with the remodeling of intracellular Ca²⁺ homeostasis with aging, thus providing a simplistic model for investigating Ca²⁺ remodeling in aging. In vitro aged neurons show increased resting cytosolic Ca²⁺ concentration, enhanced Ca²⁺ store content, and Ca²⁺ release from the endoplasmic reticulum (ER). Ca²⁺ transfer from the endoplasmic reticulum (ER) to mitochondria is also enhanced. Aged neurons also show decreased store-operated Ca²⁺ entry (SOCE), a Ca²⁺ entry pathway related to memory storage. At the molecular level, in vitro remodeling is associated with changes in the expression of Ca²⁺ channels resembling in vivo aging, including changes in N-methyl-D-aspartate NMDA receptor and inositol 1,4,5-trisphosphate (IP₃) receptor isoforms, increased expression of the mitochondrial calcium uniporter (MCU), and decreased expression of Orai1/Stim1, the molecular players involved in SOCE. Additionally, Aβo treatment exacerbates most of the changes observed in aged neurons and enhances susceptibility to cell death. Conversely, the solely effect of Aβo in young neurons is to increase ER–mitochondria colocalization and enhance Ca²⁺ transfer from ER to mitochondria without inducing neuronal damage. We propose that cultured rat hippocampal neurons may be a useful model to investigate Ca²⁺ remodeling in aging and in age-related neurodegenerative disorders. Full article

(This article belongs to the Special Issue 8th ECS Workshop 'Calcium Signaling in Aging and Neurodegenerative Diseases')

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17 pages, 2766 KiB

Open AccessReview

Calcium-Involved Action of Phytochemicals: Carotenoids and Monoterpenes in the Brain

by Jowita Rzajew, Tomasz Radzik and Elzbieta Rebas

Int. J. Mol. Sci. 2020, 21(4), 1428; https://doi.org/10.3390/ijms21041428 - 20 Feb 2020

Cited by 14 | Viewed by 4819

Abstract

Background: Neurodegenerative and mood disorders represent growing medical and social problems, many of which are provoked by oxidative stress, disruption in the metabolism of various neurotransmitters, and disturbances in calcium homeostasis. Biologically active plant compounds have been shown to exert a positive impact [...] Read more.

Background: Neurodegenerative and mood disorders represent growing medical and social problems, many of which are provoked by oxidative stress, disruption in the metabolism of various neurotransmitters, and disturbances in calcium homeostasis. Biologically active plant compounds have been shown to exert a positive impact on the function of calcium in the central nervous system. Methods: The present paper reviews studies of naturally occurring terpenes and derivatives and the calcium-based aspects of their mechanisms of action, as these are known to act upon a number of targets linked to neurological prophylaxis and therapy. Results: Most of the studied phytochemicals possess anticancer, antioxidative, anti-inflammatory, and neuroprotective properties, and these have been used to reduce the risk of or treat neurological diseases. Conclusion: The neuroprotective actions of some phytochemicals may employ mechanisms based on regulation of calcium homeostasis and should be considered as therapeutic agents. Full article

(This article belongs to the Special Issue 8th ECS Workshop 'Calcium Signaling in Aging and Neurodegenerative Diseases')

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24 pages, 1932 KiB

Open AccessReview

Intracellular Calcium Dysregulation by the Alzheimer’s Disease-Linked Protein Presenilin 2

by Luisa Galla, Nelly Redolfi, Tullio Pozzan, Paola Pizzo and Elisa Greotti

Int. J. Mol. Sci. 2020, 21(3), 770; https://doi.org/10.3390/ijms21030770 - 24 Jan 2020

Cited by 45 | Viewed by 4941

Abstract

Alzheimer’s disease (AD) is the most common form of dementia. Even though most AD cases are sporadic, a small percentage is familial due to autosomal dominant mutations in amyloid precursor protein (APP), presenilin-1 (PSEN1), and presenilin-2 (PSEN2) [...] Read more.

Alzheimer’s disease (AD) is the most common form of dementia. Even though most AD cases are sporadic, a small percentage is familial due to autosomal dominant mutations in amyloid precursor protein (APP), presenilin-1 (PSEN1), and presenilin-2 (PSEN2) genes. AD mutations contribute to the generation of toxic amyloid β (Aβ) peptides and the formation of cerebral plaques, leading to the formulation of the amyloid cascade hypothesis for AD pathogenesis. Many drugs have been developed to inhibit this pathway but all these approaches currently failed, raising the need to find additional pathogenic mechanisms. Alterations in cellular calcium (Ca²⁺) signaling have also been reported as causative of neurodegeneration. Interestingly, Aβ peptides, mutated presenilin-1 (PS1), and presenilin-2 (PS2) variously lead to modifications in Ca²⁺ homeostasis. In this contribution, we focus on PS2, summarizing how AD-linked PS2 mutants alter multiple Ca²⁺ pathways and the functional consequences of this Ca²⁺ dysregulation in AD pathogenesis. Full article

(This article belongs to the Special Issue 8th ECS Workshop 'Calcium Signaling in Aging and Neurodegenerative Diseases')

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28 pages, 3377 KiB

Open AccessReview

The Puzzling Role of Neuron-Specific PMCA Isoforms in the Aging Process

by Tomasz Boczek, Tomasz Radzik, Bozena Ferenc and Ludmila Zylinska

Int. J. Mol. Sci. 2019, 20(24), 6338; https://doi.org/10.3390/ijms20246338 - 16 Dec 2019

Cited by 13 | Viewed by 5318

Abstract

The aging process is a physiological phenomenon associated with progressive changes in metabolism, genes expression, and cellular resistance to stress. In neurons, one of the hallmarks of senescence is a disturbance of calcium homeostasis that may have far-reaching detrimental consequences on neuronal physiology [...] Read more.

The aging process is a physiological phenomenon associated with progressive changes in metabolism, genes expression, and cellular resistance to stress. In neurons, one of the hallmarks of senescence is a disturbance of calcium homeostasis that may have far-reaching detrimental consequences on neuronal physiology and function. Among several proteins involved in calcium handling, plasma membrane Ca²⁺-ATPase (PMCA) is the most sensitive calcium detector controlling calcium homeostasis. PMCA exists in four main isoforms and PMCA2 and PMCA3 are highly expressed in the brain. The overall effects of impaired calcium extrusion due to age-dependent decline of PMCA function seem to accumulate with age, increasing the susceptibility to neurotoxic insults. To analyze the PMCA role in neuronal cells, we have developed stable transfected differentiated PC12 lines with down-regulated PMCA2 or PMCA3 isoforms to mimic age-related changes. The resting Ca²⁺ increased in both PMCA-deficient lines affecting the expression of several Ca²⁺-associated proteins, i.e., sarco/endoplasmic Ca²⁺-ATPase (SERCA), calmodulin, calcineurin, GAP43, CCR5, IP₃Rs, and certain types of voltage-gated Ca²⁺ channels (VGCCs). Functional studies also demonstrated profound changes in intracellular pH regulation and mitochondrial metabolism. Moreover, modification of PMCAs membrane composition triggered some adaptive processes to counterbalance calcium overload, but the reduction of PMCA2 appeared to be more detrimental to the cells than PMCA3. Full article

(This article belongs to the Special Issue 8th ECS Workshop 'Calcium Signaling in Aging and Neurodegenerative Diseases')

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7 pages, 223 KiB

Open AccessMeeting Report

Calcium Signaling in Aging and Neurodegenerative Diseases 2019

by Luísa Cortes, João Malva, Ana Cristina Rego and Cláudia F. Pereira

Int. J. Mol. Sci. 2020, 21(3), 1125; https://doi.org/10.3390/ijms21031125 - 7 Feb 2020

Cited by 12 | Viewed by 3136

Abstract

The European Calcium Society (ECS) workshop, which is held every 2 years, is a dedicated meeting of scientists interested in the elucidation of the action of calcium binding, calcium signaling and the study of proteins and organelles, such as mitochondria and endoplasmic reticulum, [...] Read more.

The European Calcium Society (ECS) workshop, which is held every 2 years, is a dedicated meeting of scientists interested in the elucidation of the action of calcium binding, calcium signaling and the study of proteins and organelles, such as mitochondria and endoplasmic reticulum, thereby involved, either in health and disease conditions. The 8th edition of the ECS workshop was organized by a group of researchers from the University of Coimbra, Portugal, in close collaboration with ECS board members. Thanks to the central role of “Calcium Signaling in Aging and Neurodegenerative Disorders”, the ECS 2019 workshop was attended by 62 experts who presented their results in a plenary lecture and five regular symposia, two oral communication sessions and two poster sessions, followed by a hands-on session on calcium imaging. All the scientific and social events were fully participated by the scientific community that allowed a close and fruitful interaction and discussion between junior researchers and senior experts in the field. In this report, the contributions in individual sessions are summarized. Full article

(This article belongs to the Special Issue 8th ECS Workshop 'Calcium Signaling in Aging and Neurodegenerative Diseases')

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