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Reinald Pamplona - One of the best experts on this subject based on the ideXlab platform.
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Cell Stress induces TDP-43 pathological changes associated with ERK1/2 dysfunction: implications in ALS
Acta Neuropathologica, 2011Co-Authors: Victòria Ayala, Ana Belén Granado-serrano, Daniel Cacabelos, Alba Naudí, Ekaterina V. Ilieva, Jordi Boada, Víctor Caraballo-miralles, Jerònia Lladó, Isidro Ferrer, Reinald PamplonaAbstract:TDP-43 has been implicated in the pathogenesis of amyotrophic lateral sclerosis and other neurodegenerative diseases. Here we demonstrate, using neuronal and spinal cord organotypic culture models, that chronic excitotoxicity, oxidative Stress, proteasome dysfunction and endoplasmic reticulum Stress mechanistically induce mislocalization, phosphorylation and aggregation of TDP-43. This is compatible with a lack of function of this protein in the nucleus, specially in motor neurons. The relationship between Cell Stress and pathological changes of TDP-43 also includes a dysfunction in the survival pathway mediated by mitogen-activated protein kinase/extraCellular signal-regulated kinases (ERK1/2). Thus, under Stress conditions, neurons and other spinal cord Cells showed cytosolic aggregates containing ERK1/2. Moreover, aggregates of abnormal phosphorylated ERK1/2 were also found in the spinal cord in amyotrophic lateral sclerosis (ALS), specifically in motor neurons with abnormal immunoreactive aggregates of phosphorylated TDP-43. These results demonstrate that Cellular Stressors are key factors in neurodegeneration associated with TDP-43 and disclose the identity of ERK1/2 as novel players in the pathogenesis of ALS.
Brian Henderson - One of the best experts on this subject based on the ideXlab platform.
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Monocyte cytokine synthesis in response to extraCellular Cell Stress proteins suggests these proteins exhibit network behaviour
Cell Stress and Chaperones, 2014Co-Authors: Frank Kaiser, Andrew Steptoe, Stephen Thompson, Brian HendersonAbstract:Human peripheral blood monocytes were exposed to single or pairs of Cell Stress proteins (CSPs), specifically Hsp10, Hsp27, Hsp60 and Hsp70—the former two having anti-inflammatory actions while the latter pair being assumed to be pro-inflammatory in activity. This study was to test if these proteins exhibited any network behaviour. To control for possible lipopolysaccharide contamination, polymyxin B was used. Surprisingly, at concentrations higher than 1 μg/ml, polymyxin B itself could induce cytokine synthesis. A number of commercial sources of the molecular chaperones were tested, and marked variations in monocyte cytokine synthesis were found. All four CSPs stimulated the same profile of IL-1/IL-6 synthesis and IL-10/TNF-α synthesis although the kinetics of production of these two pairs of cytokines were very different. A key question was whether extraCellular molecular chaperones exhibited network behaviour. To test this, monocytes were cultured with suboptimal concentrations of single CSP and pairs of CSP to look for additive, synergistic or antagonistic Cell responses. The major finding was that pairs of molecular chaperones, including chaperones thought to stimulate monocyte cytokine synthesis, could produce significant antagonistic Cellular responses. This demonstrates that extraCellular CSPs constitute an additional potent layer within the complex cytokine network and furthermore suggests that monocytes have evolved to dampen their immune responses upon exposure to extraCellular networks of CSPs—perhaps as a mechanism for protecting Cells against detrimental Cellular Stress responses.
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Do reciprocal interactions between Cell Stress proteins and cytokines create a new intra-/extra-Cellular signalling nexus?
Cell Stress and Chaperones, 2013Co-Authors: Brian Henderson, Frank KaiserAbstract:Cytokine biology began in the 1950s, and by 1988, a large number of cytokines, with a myriad of biological actions, had been discovered. In 1988, the basis of the protein chaperoning function of the heat shock, or Cell Stress, proteins was identified, and it was assumed that this was their major activity. However, since this time, evidence has accumulated to show that Cell Stress proteins are secreted by Cells and can stimulate Cellular cytokine synthesis with the generation of pro- and/or anti-inflammatory cytokine networks. Cell Stress can also control cytokine synthesis, and cytokines are able to induce, or even inhibit, the synthesis of selected Cell Stress proteins and may also promote their release. How Cell Stress proteins control the formation of cytokines is not understood and how cytokines control Cell Stress protein synthesis depends on the Cellular compartment experiencing Stress, with cytoplasmic heat shock factor 1 (HSF1) having a variety of actions on cytokine gene transcription. The endoplasmic reticulum unfolded protein response also exhibits a complex set of behaviours in terms of control of cytokine synthesis. In addition, individual intraCellular Cell Stress proteins, such as Hsp27 and Hsp90, have major roles in controlling Cellular responses to cytokines and in controlling cytokine synthesis in response to exogenous factors. While still confusing, the literature supports the hypothesis that Cell Stress proteins and cytokines may generate complex intra- and extra-Cellular networks, which function in the control of Cells to external and internal Stressors and suggests the Cell Stress response as a key parameter in cytokine network generation and, as a consequence, in control of immunity.
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A Brief Introduction to the Eukaryotic Cell Stress Proteins
Heat Shock Proteins, 2013Co-Authors: Brian HendersonAbstract:The discovery of the heat shock response in Drosophila in the early 1960s led on to the elucidation of the Cell Stress response and the discovery of proteins of molecular mass of 10, 20, 40, 60, 70 and 90 kDa, amongst others, and which were termed the heat shock proteins. Beginning in the late 1970s, and continuing up to the present day, has been the identification of these heat shock/Cell Stress proteins and their mechanism of action, both as protein-folding proteins and as proteins with a range of other functions in various compartments of the Cell and in the interCellular space. In addition to functioning as molecular chaperones, the heat shock/Cell Stress proteins can also function as Cell surface receptors and as interCellular signalling molecules. This growing diversity of the biological functions of the Cell Stress proteins reveals that these proteins play roles in all aspects of Cellular physiology and that these functions also contribute to whole body homeostatic control and to the dark side of human pathophysiology.
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Proteotoxic Stress and circulating Cell Stress proteins in the cardiovascular diseases
Cell Stress and Chaperones, 2012Co-Authors: Brian Henderson, A. Graham PockleyAbstract:The cardiovasculature is one of the major body systems and probably the one most exposed to Stress. There is clear evidence that increasing levels of Cell Stress proteins within the heart is cardioprotective. In addition, there is rapidly emerging evidence that secreted Cell Stress proteins play a role in the function of the cardiovascular tissues. Those secreted proteins have three potential functions: (1) as normal homeostatic cardiovascular signals (e.g. protein disulphide isomerase); (2) as anti-inflammatory molecules, which are able to inhibit cardiovascular pathology (e.g. Hsp27); and (iii) as pro-inflammatory signals that can induce and promote cardiovascular pathology (e.g. Hsp60). As all of these various proteins may be released—at different rates—and in different cardiovascular diseases—we need to consider the cohort of potential secreted Cell Stress proteins as a dynamic system (network) that can aid and/or damage the equally dynamic cardiovascular system.
Victòria Ayala - One of the best experts on this subject based on the ideXlab platform.
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Cell Stress induces TDP-43 pathological changes associated with ERK1/2 dysfunction: implications in ALS
Acta Neuropathologica, 2011Co-Authors: Victòria Ayala, Ana Belén Granado-serrano, Daniel Cacabelos, Alba Naudí, Ekaterina V. Ilieva, Jordi Boada, Víctor Caraballo-miralles, Jerònia Lladó, Isidro Ferrer, Reinald PamplonaAbstract:TDP-43 has been implicated in the pathogenesis of amyotrophic lateral sclerosis and other neurodegenerative diseases. Here we demonstrate, using neuronal and spinal cord organotypic culture models, that chronic excitotoxicity, oxidative Stress, proteasome dysfunction and endoplasmic reticulum Stress mechanistically induce mislocalization, phosphorylation and aggregation of TDP-43. This is compatible with a lack of function of this protein in the nucleus, specially in motor neurons. The relationship between Cell Stress and pathological changes of TDP-43 also includes a dysfunction in the survival pathway mediated by mitogen-activated protein kinase/extraCellular signal-regulated kinases (ERK1/2). Thus, under Stress conditions, neurons and other spinal cord Cells showed cytosolic aggregates containing ERK1/2. Moreover, aggregates of abnormal phosphorylated ERK1/2 were also found in the spinal cord in amyotrophic lateral sclerosis (ALS), specifically in motor neurons with abnormal immunoreactive aggregates of phosphorylated TDP-43. These results demonstrate that Cellular Stressors are key factors in neurodegeneration associated with TDP-43 and disclose the identity of ERK1/2 as novel players in the pathogenesis of ALS.
Thomas E. Hughes - One of the best experts on this subject based on the ideXlab platform.
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Live-Cell Assays for Cell Stress Responses Reveal New Patterns of Cell Signaling Caused by Mutations in Rhodopsin, α-Synuclein and TDP-43.
Frontiers in Cellular Neuroscience, 2019Co-Authors: Kevin M. Harlen, Elizabeth C. Roush, Joseph E. Clayton, Scott Martinka, Thomas E. HughesAbstract:: Many neurodegenerative diseases induce high levels of sustained Cellular Stress and alter a number of Cellular processes. To examine how different mutations associated with neurodegenerative disease affect Cell Stress and signaling, we created live-Cell assays for endoplasmic reticulum (ER)-mediated Cell Stress and second messenger signaling. We first examined neurodegenerative mutations associated with direct ER Stress by exploring the effect of rhodopsin mutations on ER Stress and Ca2+ signaling. The rhodopsin P23H mutation, the most common mutation in autosomal dominant Retinitis Pigmentosa (RP), produced increased ER Stress levels compared to wild type (WT) rhodopsin. Moreover, this increase in Cell Stress correlated with blunted Ca2+ signaling in a Stress-dependent manner. Analysis of single-Cell Ca2+ signaling profiles revealed unique Ca2+ signaling responses exist in Cells expressing WT or P23H rhodopsin, consistent with the idea that second messenger signaling is affected by Cell Stress. To explore the use of the ER-Stress biosensor in neurodegenerative diseases that may not have a direct effect on ER-mediated Cell Stress, we examined how various mutants of α-synuclein and TDP-43 affected ER Stress. Mutants of both α-synuclein and TDP-43 associated with Parkinson's disease (PD) and Amyotrophic lateral sclerosis (ALS) demonstrated increased ER Stress compared to WT proteins. To examine the effect of α-synuclein and TDP-43 mutants on Cellular signaling, we created a second live-Cell assay to monitor changes in cAMP signaling during expression of various forms of α-synuclein and TDP-43. The increased Cell Stress caused by expression of the mutant proteins was accompanied by changes in phosphodiesterase activity. Both HEK293T and SH-SY5Y Cells expressing these proteins displayed a shift towards increased cAMP degradation rates, likely due to increased phosphodiesterase activity. Together these data illustrate how biosensors for Cellular Stress and signaling can provide nuanced, new views of neurodegenerative disease processes.
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Live-Cell assays for Cell Stress responses reveal new patterns of Cell signaling caused by mutations in rhodopsin, α-synuclein and TDP-43
bioRxiv, 2019Co-Authors: Kevin M. Harlen, Elizabeth C. Roush, Joseph E. Clayton, Scott Martinka, Thomas E. HughesAbstract:ABSTRACT Many neurodegenerative diseases induce high levels of sustained Cellular Stress and alter a number of Cellular processes. Genetically-encoded fluorescent biosensors are effective tools to examine neuronal activity and signaling in living Cells. To examine how different mutations associated with neurodegenerative disease affect Cell Stress and signaling we created live-Cell assays for ER-mediated Cell Stress and second messenger signaling. Analysis of the rhodopsin P23H mutation, the most common mutation in autosomal dominant Retinitis Pigmentosa, revealed increased Cell Stress levels compared to wild type rhodopsin. Moreover, this increase in Cell Stress correlated with blunted Ca2+ signaling in a Stress dependent manner. Analysis of single Cell Ca2+ signaling profiles revealed unique Ca2+ signaling responses exist in Cells expressing wild type or P23H mutants, further supporting the notion that second messenger signaling is affected by Cell Stress. To explore the use of the ER-Stress biosensor in other neurodegenerative diseases we examined how various mutants of α-synuclein and TDP-43 affected ER-mediated Cell Stress. Mutants of both α-synuclein and TDP-43 associated with Parkinson’s Disease and ALS demonstrated increases in ER-mediated Cell Stress. This increased Cell Stress was accompanied by changes in phosphodiesterase activity. Both HEK293T and SH-SY5Y Cells expressing these proteins displayed a shift towards increased cAMP degradation rates, likely due to increased phosphodiesterase activity. Together these data illustrate how biosensors can provide nuanced, new views of neurodegenerative disease processes.
Mario D. Galigniana - One of the best experts on this subject based on the ideXlab platform.
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When the Cell Stress Society International became South American: meeting report of the IX International Workshop on the Molecular Biology of Stress Responses
Cell Stress and Chaperones, 2013Co-Authors: Mario D. GalignianaAbstract:The International Workshop on the Molecular Biology of the Stress Response organized by the Cell Stress Society International was held in Porto Alegre, Brazil, on May 27–30, 2012, as part of the development of the Latin American Chapter of the Society, a superb initiative headed by Drs. Antonio De Maio and Larry Hightower. The meeting took place in the wonderful facilities of the Pontifícia Universidade do Rio Grande do Sul (PUCRS) and was warmly chaired by Professor Cristina Bonorino. Thirty-four invited speakers presented their work to more than 200 scientists and, even more importantly, to 150 registered students, who were the main beneficiaries of the meeting. The first day of the workshop was dedicated to an educational program for students, young investigators, and participants who were unfamiliar with the field of molecular chaperones and the Stress response. Speakers in this pre-workshop were Dr. Harm Kampinga, Dr. Lea Sistonen, Dr. Larry Hightower, Dr. Ivor Benjamin, Dr. Daniel Ciocca, and Dr. Linda Hendershot. Then, the scientific sessions discussed below followed.