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Cell Death Process (cell + death_process)
Selected AbstractsDoes tissue transglutaminase play a role in Huntington's disease?JOURNAL OF NEUROCHEMISTRY, Issue 2002G. V. W. Johnson Tissue transglutaminase (tTG) catalyzes the incorporation of polyamines into substrates, or the formation of isopeptide bonds. tTG also binds and hydrolyzes GTP/ATP. Huntington's disease (HD) is caused by a pathological expansion of the polyglutamine domain in the protein huntingtin (htt). Because a polypeptide bound Gln residue is the primary determining factor for a tTG substrate, it has been hypothesized that due to the increase in Gln content, mutant htt may modified by tTG and this event may contribute to the pathogenesis of HD, possibly by facilitating the formation of htt aggregates. tTG is increased in HD, suggesting involvement in the pathogenic process. However, tTG is not required for aggregate formation. Further, tTG is excluded from htt aggregates and increasing or decreasing tTG has no effect on the frequency or localization of the aggregates. Considering these and other data, tTG is unlikely to play a major role in the formation of htt inclusions in HD brain. tTG may play a role in modulating neuronal cell death in response to specific stressors. If a stress increases the transamidating activity of tTG (e.g. increases in Ca++ levels), then tTG facilitates the cell death process. In contrast, if a stress does not result in an increase in the transamidating activity of tTG, then tTG protects against cell death. The protective effects of tTG are independent of its transamidating and hence likely dependent on its GTP/ATP binding and hydrolytic activity. Therefore the increase in tTG levels in HD brain could either be helpful or harmful depending on the cellular mechanisms that contribute to neuronal death. Acknowledgements:, Supported by NIH grant AG12396. [source] Characterization of the caspase cascade in a cell culture model of SOD1-related familial amyotrophic lateral sclerosis: expression, activation and therapeutic effects of inhibitionNEUROPATHOLOGY & APPLIED NEUROBIOLOGY, Issue 5 2005S. Sathasivam There is increasing evidence that apoptosis or a similar programmed cell death pathway is the mechanism of cell death responsible for motor neurone degeneration in amyotrophic lateral sclerosis. Knowledge of the relative importance of different caspases in the cell death process is at present incomplete. In addition, there is little information on the critical point of the death pathway when the process of dying becomes irreversible. In this study, using the well-established NSC34 motor neurone-like cell line stably transfected with empty vector, normal or mutant human Cu-Zn superoxide dismutase (SOD1), we have characterized the activation of the caspase cascade in detail, revealing that the activation of caspases-9, -3 and -8 are important in motor neurone death and that the presence of mutant SOD1 causes increased activation of components of the apoptotic cascade under both basal culture conditions and following oxidative stress induced by serum withdrawal. Activation of the caspases identified in the cellular model has been confirmed in the G93A SOD1 transgenic mice. Furthermore, investigation of the effects of anti-apoptotic neuroprotective agents including specific caspase inhibitors, minocycline and nifedipine, have supported the importance of the mitochondrion-dependent apoptotic pathway in the death process and revealed that the upstream caspase cascade needs to be inhibited if useful neuro-protection is to be achieved. [source] Apoptosis in amyotrophic lateral sclerosis: a review of the evidenceNEUROPATHOLOGY & APPLIED NEUROBIOLOGY, Issue 4 2001S. Sathasivam Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease primarily affecting the upper and lower motor neurones of the central nervous system. Recently, a lot of interest has been generated by the possibility that a mechanism of programmed cell death, termed apoptosis, is responsible for the motor neurone degeneration in this condition. Apoptosis is regulated through a variety of different pathways which interact and eventually lead to controlled cell death. Apart from genetic regulation, factors involved in the control of apoptosis include death receptors, caspases, Bcl-2 family of oncoproteins, inhibitor of apoptosis proteins (IAPs), inhibitors of IAPs, the p53 tumour suppressor protein and apoptosis-related molecules. The first part of this article will give an overview of the current knowledge of apoptosis. In the second part of this review, we will examine in detail the evidence for and against the contribution of apoptosis in motor neurone cell death in ALS, looking at cellular-, animal- and human post-mortem tissue-based models. In a chronic neurodegenerative disease such as ALS, conclusive evidence of apoptosis is likely to be difficult to detect, given the rapidity of the apoptotic cell death process in relation to the relatively slow time course of the disease. Although a complete picture of motor neurone death in ALS has not been fully elucidated, there is good and compelling evidence that a programmed cell death pathway operates in this disorder. The strongest body of evidence supporting this comes from the findings that, in ALS, changes in the levels of members of the Bcl-2 family of oncoproteins results in a predisposition towards apoptosis, there is increased expression or activation of caspases-1 and -3, and the dying motor neurones in human cases exhibit morphological features reminiscent of apoptosis. Further supporting evidence comes from the detection of apoptosis-related molecules and anti-Fas receptor antibodies in human cases of ALS. However, the role of the p53 protein in cell death in ALS is at present unclear. An understanding of the mechanism of programmed cell death in ALS may provide important clues for areas of potential therapeutic intervention for neuroprotection in this devastating condition. [source] Mitochondrial morphology transition is an early indicator of subsequent cell death in ArabidopsisNEW PHYTOLOGIST, Issue 1 2008Iain Scott Summary ,,Mitochondrial morphology and dynamics were investigated during the onset of cell death in Arabidopsis thaliana. Cell death was induced by either chemical (reactive oxygen species (ROS)) or physical (heat) shock. ,,Changes in mitochondrial morphology in leaf tissue, or isolated protoplasts, each expressing mitochondrial-targeted green fluorescent protein (GFP), were observed by epifluorescence microscopy, and quantified. ,,Chemical induction of ROS production, or a mild heat shock, caused a rapid and consistent change in mitochondrial morphology (termed the mitochondrial morphology transition) that preceded cell death. Treatment of protoplasts with a cell-permeable superoxide dismutase analogue, TEMPOL, blocked this morphology change. Incubation of protoplasts in micromolar concentrations of the calcium channel-blocker lanthanum chloride, or the permeability transition pore inhibitor cyclosporin A, prevented both the mitochondrial morphology transition and subsequent cell death. ,,It is concluded that the observed mitochondrial morphology transition is an early and specific indicator of cell death and is a necessary component of the cell death process. [source] Fundamentals of neuronal apoptosis relevant to pediatric anesthesiaPEDIATRIC ANESTHESIA, Issue 5 2010MORGAN BLAYLOCK PhD Summary The programmed cell death or apoptosis is a complex biochemical process that has risen to prominence in pediatric anesthesia. Preclinical studies report a dose-dependant neuronal apoptosis during synaptogenesis following exposure to intravenous and volatile anesthetic agents. Although emerging clinical data do not universally indicate an increased neurodegenerative risk of general anesthesia in early human life, a great deal of uncertainty was created within the pediatric anesthesia community. This was at least partially caused by the demand of understanding of basic science concepts and knowledge of apoptosis frequently out of reach to the clinician. It is, however, important for the pediatric anesthesiologist to be familiar with the basic science concepts of neuronal apoptosis to be able to critically evaluate current and future preclinical data in this area and future clinical studies. This current review describes the extrinsic and intrinsic pathways involved in the cell death process and discusses techniques commonly employed to determine apoptosis. In addition, potential mechanisms of anesthesia-induced neuronal apoptosis are illustrated in this review. [source] Hybrid Lethality in Interspecific F1 Hybrid Nicotiana gossei×N. tabacum Involves a MAP-Kinases Signalling CascadePLANT BIOLOGY, Issue 3 2007M. Mino Abstract: A cultured cell line, GTH4 (Nicotiana gossei Domin ×N. tabacum L.), which exhibits hybrid lethality, died at 26 °C, but not at 37 °C. Pharmacological experiments using inhibitors of protein phosphatases and protein kinases indicated the involvement of a protein kinase signalling pathway in the cell death process. Immunoblot analysis revealed that salicylic acid-induced protein kinase (SIPK) was phosphorylated soon after the shift in temperature from 37 °C to 26 °C. Cultured cells of the hybrid of N. gossei× transgenic N. tabacum harboring a steroid (dexamethasone; DEX)-inducible NtMEK2DD or NtMEK2KR, constitutively active and inactive forms of NtMEK2, respectively, were established. Induction of NtMEK2DD by DEX in the hybrid cells induced the activation of SIPK, the generation of hydrogen peroxide (H2O2), and cell death at 37 °C. The activation of SIPK, generation of H2O2, and cell death at 26 °C were compromised by DEX treatment in hybrid cells harbouring NtMEK2KR. This study provides evidence for the involvement of MAPK signalling in the regulation of cell death in hybrids. [source] SIPK signaling controls multiple components of harpin-induced cell death in tobaccoTHE PLANT JOURNAL, Issue 3 2005Marcus A. Samuel Summary Harpin from Pseudomonas syringae pv. phaseolicola (HrpZ) elicits a rapid cell death response in tobacco plants. Multiple signaling components, including mitogen-activated protein kinase (MAPK), reactive oxygen species (ROS) and salicylic acid (SA), have been reported to be involved in this cell death process, but the interaction between these molecules is poorly understood. Here we show through utilizing plants manipulated in SIPK expression levels that lack of SIPK results in increased sensitivity to harpin with concomitant accumulation of higher levels of ROS. Conversely, SIPK-overexpressing plants show reduced sensitivity to harpin relative to wild-type plants, and display reduced ROS accumulation. Harpin-induced cell death was found to be conditional on the ability of the plant to accumulate SA, whereas harpin induction of MAPK activation and ROS accumulation are not. However, harpin-induced ROS accumulation is required for activation of SIPK and wound-induced protein kinase. Transcriptional profiling revealed that suppression of SIPK signaling also affects early expression of a range of pathogen- and stress-responsive genes during harpin challenge. [source] Streptococcus pyogenes induces oncosis in macrophages through the activation of an inflammatory programmed cell death pathwayCELLULAR MICROBIOLOGY, Issue 1 2009Oliver Goldmann Summary Macrophages are crucial components of the host defence against Streptococcus pyogenes. Here, we demonstrate the ability of S. pyogenes to kill macrophages through the activation of an inflammatory programmed cell death pathway. Macrophages exposed to S. pyogenes exhibited extensive cytoplasmic vacuolization, cellular and organelle swelling and rupture of the plasma membrane typical of oncosis. The cytotoxic effect of S. pyogenes on macrophages is mediated by the streptococcal cytolysins streptolysin S and streptolysin O and does not require bacterial internalization. S. pyogenes -induced death of macrophages was not affected by the addition of osmoprotectant, implicating the activation of an orchestrated cell death pathway rather than a simple osmotic lysis. This programme cell death pathway involves the loss of mitochondria transmembrane potential (,,m) and was inhibited by the addition of exogenous glycine, which has been shown to prevent necrotic cell death by blocking the opening of death channels in the plasma membrane. The production of reactive oxygen species and activation of calpains were identified as mediators of the cell death process. We conclude that activation of the inflammatory programmed cell death pathway in macrophages could constitute an important pathogenic mechanism by which S. pyogenes evades host immune defences and causes disease. [source] Low-affinity neurotrophin receptor with targeted mutation of exon 3 is capable of mediating the death of axotomized neuronsCLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 4 2003Simon S Murray Summary 1.,In vivo studies have shown that the low-affinity 75 kDa neurotrophin receptor (p75NTR) is involved in axotomy-induced cell death of sensory and motor neurons. To further examine the importance of p75NTR in mediating neuronal death in vivo, we examined the effect of axotomy in the p75NTR-knockout mouse, which has a disrupted ligand-binding domain. 2.,The extent of sensory and motor neuron loss in the p75NTR-knockout mouse following axotomy was not significantly different to that in wild-type mice. This suggests that disruption of the ligand-binding domain is insufficient to block the cell death process in axotomized neurons. 3.,Immunohistochemical studies showed that axotomized neurons continue to express this mutant receptor with its intracellular death-signalling moiety intact. 4.,Treatment with antisense oligonucleotides targeted against p75NTR resulted in significant reduction in the loss of axotomized neurons in the knockout mouse. 5.,These data suggest that the intracellular domain of p75NTR is essential for death-signalling and that p75NTR can signal apoptosis, despite a disrupted ligand-binding domain. [source] Neuroprotective Strategies to Avert Seizure-Induced Neurodegeneration in EpilepsyEPILEPSIA, Issue 2007Janice R. Naegele Summary:, Neurodegeneration in limbic circuits is a hallmark feature of chronic temporal lobe epilepsy (TLE). Studies in experimental animal models and human patients indicate that seizure-induced neuronal injury involves some active, as well as passive cell death processes. Experimental approaches that inhibit active steps in cell death programs have been shown to reduce neuronal cell death and sclerosis, but not to prevent epileptogenesis in animal models of TLE. These findings suggest that we need additional research using both animal models and brain slices from human patients to understand the pathological mechanisms underlying seizure generation. Such comparative studies will also aid in evaluating the potential therapeutic value of inhibiting cell death in seizure disorders. [source] Delayed treatment with a p53 inhibitor enhances recovery in stroke brain,ANNALS OF NEUROLOGY, Issue 5 2009Yu Luo PhD Objective Cerebral ischemia can activate endogenous reparative processes, such as proliferation of endogenous neural progenitor cells (NPCs) in the subventricular zone (SVZ). Most of these new cells die shortly after injury. The purpose of this study was to examine a novel strategy for treatment of stroke at 1 week after injury by enhancing the survival of ischemia-induced endogenous NPCs in SVZ. Methods Adult rats were subjected to a 90-minutes middle cerebral artery occlusion. A p53 inhibitor pifithrin-, (PFT-,) was administered to stroke rats from days 6 to 9 after middle cerebral artery occlusion. Locomotor behavior was measured using an activity chamber. Proliferation, survival, migration, and differentiation of endogenous NPCs were examined using quantitative reverse transcription polymerase chain reaction, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling, and immunohistochemistry. Results PFT-, enhanced functional recovery as assessed by a significant increase in multiple behavioral measurements. Delayed PFT-, treatment had no effect on the cell death processes in the lesioned cortical region. However, it enhanced the survival of SVZ progenitor cells, and promoted their proliferation and migration. PFT-, inhibited the expression of a p53-dependent proapoptotic gene, termed PUMA (p53-upregulated modulator of apoptosis), within the SVZ of stroke animals. The enhancement of survival/proliferation of NPCs was further found in SVZ neurospheres in tissue culture. PFT-, dose-dependently increased the number and size of new neurosphere formation. Interpretation Delayed treatment with a p53 inhibitor PFT-, is able to modify stroke-induced endogenous neurogenesis and improve the functional recovery in stroke animals. Ann Neurol 2009;65:520,530 [source] | |||||||||||||