Prostaglandin D2 induces programmed cell death in Trypanosoma brucei bloodstream form

Figarella, Katherine; Rawer, Marc; Uzcátegui, Néstor L.; Kubata, Bruno Kilunga; Lauber, Kirsten; Madeo, Frank; Wesselborg, Sebastian; Duszenko, Michael

doi:10.1038/sj.cdd.4401564

Cited by 81 publications

(99 citation statements)

References 64 publications

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“…Likewise, similar structures have been reported in cells that undergo autophagy after inhibition of sterol synthesis (Coppens and Courtoy, 1995). Enlarged flagellar pockets and mitochondrial pocket distention have been reported in dying trypanosome cells (Figarella et al, 2005;Lazardi et al, 1990;Pearson et al, 2000;Welburn et al, 1996), although mitochondrial distention might also be due to sensitivity of the trypanosome mitochondrial membrane to lipid perturbation, as has been observed after ergosterol depletion (Coppens and Courtoy, 2000).…”

Section: Vesicular Trafficking Defects and Drmsmentioning

confidence: 79%

Sphingolipid synthesis is necessary for kinetoplast segregation and cytokinesis in Trypanosoma brucei

Fridberg

Olson

Nakayasu

et al. 2008

Journal of Cell Science

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Sphingolipids and their metabolites have been thought crucial for cell growth and cell cycle progression, membrane and protein trafficking, signal transduction, and formation of lipid rafts; however, recent studies in trypanosomes point to the dispensability of sphingolipids in some of these processes. In this study, we explore the requirements for de novo sphingolipid biosynthesis in the insect life cycle stage of the African trypanosome Trypanosoma brucei by inhibiting the enzyme serine palmitoyltransferase (SPT2) by using RNA interference or treatment with a potent SPT2 inhibitor myriocin. Mass spectrometry revealed that upon SPT2 inhibition, the parasites contained substantially reduced levels of inositolphosphorylceramide. Although phosphatidylcholine and cholesterol levels were increased to compensate for this loss, the cells were ultimately not viable. The most striking result of sphingolipid reduction in procyclic T. brucei was aberrant cytokinesis, characterized by incomplete cleavage-furrow formation, delayed kinetoplast segregation and emergence of cells with abnormal DNA content. Organelle replication continued despite sphingolipid depletion, indicating that sphingolipids act as second messengers regulating cellular proliferation and completion of cytokinesis. Distention of the mitochondrial membrane, formation of multilamellar structures within the mitochondrion and near the nucleus, accumulation of lipid bodies and, less commonly, disruption of the Golgi complex were observed after prolonged sphingolipid depletion. These findings suggest that some aspects of vesicular trafficking may be compromised. However, flagellar membrane targeting and the association of the flagellar membrane protein calflagin with detergent-resistant membranes were not affected, indicating that the vesicular trafficking defects were mild. Our studies indicate that sphingolipid biosynthesis is vital for cell cycle progression and cell survival, but not essential for the normal trafficking of flagellar membrane-associated proteins or lipid raft formation in procyclic T. brucei.

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Section: Vesicular Trafficking Defects and Drmsmentioning

confidence: 79%

Sphingolipid synthesis is necessary for kinetoplast segregation and cytokinesis in Trypanosoma brucei

Fridberg

Olson

Nakayasu

et al. 2008

Journal of Cell Science

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“…However, one has to keep in mind that PGD 2 binds very effectively to serum proteins, which are indispensable for axenic cultivation of the parasite [2]. We thus still consider PGD 2 as a physiological apoptosis inducer for an effective cell density control especially during brain infection [22].…”

Section: Discussionmentioning

confidence: 99%

“…Beside microscopic techniques including fluorescence and electron microscopy, we used especially flow cytometry analysis to detect characteristic intracellular apoptosis markers. As described earlier, increased levels of reactive oxygen species (ROS) like H 2 O 2 or hydroxyl radicals is indicative of caspase-independent apoptosis in trypanosomes [2] as well as in higher eukaryotes [41]. We here used different reagents to characterize which ROS is formed due to PGD 2 or STS induced apoptosis.…”

Section: +mentioning

confidence: 99%

“…In T. brucei, PGD 2 is produced and secreted by the stumpy bloodform and induces an apoptosis-like cell death which includes intra-cellular ROS formation, phosphatidylserine exposure, loss of mitochondrial membrane potential and DNA degradation [3]. The stumpy bloodform was also shown to be more sensitive to PGD 2 than the slender bloodform, suggesting that the physiological function of PGD 2 is related to the parasite's cell density regulation and acts therefore in favour of a balanced parasite-host interrelationship [2] [22].…”

Section: Introductionmentioning

confidence: 99%

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Staurosporine-Induced Cell Death in <em>Trypanosoma brucei</em> and the Role of Endonuclease G during Apoptosis

Barth¹,

Bruges²,

Meiwes³

et al. 2014

OJApo

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Apoptosis in single-cell organisms like Trypanosoma or Leishmania was characterized in several studies in the last few years [1]- [4]. Cell death in these caspase lacking protozoa is still poorly understood and a conclusive apoptotic pathway has not been identified so far. In the work presented here, we studied the effects of prostaglandin D2 and staurosporine induced cell death in bloodforms of Trypanosoma brucei in a time dependent manner and focused on the role of a nuclease similar to endonuclease G of higher eukaryotes. We found that these parasites undergo apoptotic cell death as demonstrated by the appearance of several canonical hallmarks of apoptosis in higher eukaryotes, but that different stimuli induce remarkable differences in the way these cells die. We compared the effects of prostaglandin D2 and staurosporine in trypanosomes with and without endonuclease G overexpression by flow cytometric and electron microscopic methods with the result that endonuclease G overexpression led to a significant modification of intracellular organelles and accelerated apoptotic cell death in prostaglandin D2 or staurosporine treated cells. Our results demonstrate that different stimuli induce apoptosis even in these ancient organisms in different caspase-independent ways. Whereas central processes of apoptosis like ROS formation, loss of mitochondrial membrane potential, endonuclease G release, phosphatidylserine exposure and DNA fragmentation appeared in the same chronology during treatment with either one of both drugs, other effects like cell cycle arrest or change of cell shape occurred only in the case of prostaglandin D2 or staurosporine treatment. We conclude from these results that trypanosomes react to stimuli of apoptosis with the concerted action of cellular responses but cannot control the final outcome if additional stress, as in the case of staurosporine, is superimposed.

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“…These events cause further microglial activation; it is this sustained activation of microglia that results in progressive neurodegeneration (Aloisi, 2001;Gehrmann et al, 1995;Nyoman & Darmadipura, 2007;Rai et al, 2013). The IL-1, TNF and ROS/RNS also promote neurodegeneration by up-regulating proinflammatory transcription factor (NF-B), COX-2 and activating apoptotic pathways (Albrecht et al, 2007;Fan et al, 2008;Figarella et al, 2005;Ke et al, 2007;Parikh et al, 2000).…”

Section: Discussionmentioning

confidence: 99%

A comparison of neurodegeneration linked with neuroinflammation in different brain areas of rats after intracerebroventricular colchicine injection

Sil

Ghosh

Sanyal

et al. 2015

Journal of Immunotoxicology

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Colchicine induces neurodegeneration, but the extent of neurodegeneration in different areas of the brain in relation to neuroinflammation remains unclear. Such information may be useful to allow for the development of a model to compare colchicine-induced neurodegeneration with other neurodegenerative diseases such as Alzheimer's Disease (AD). The present study was designed to investigate the extent of neurodegeneration along with neuroinflammation in different areas of the brain, e.g. frontal cortex, parietal cortex, occipital cortex, corpus striatum, amygdala and hippocampus, in rats along with memory impairment 21 days after a single intracerebroventricular (icv) injection of colchicine. Memory parameters were measured before and after icv colchicine injection in all test groups of rats (control, sham-operated, colchicineinjected [ICIR] rats). On Day 21 post-injection, rats from all groups were anesthesized and tissues from the various brain areas were collected for assessment of biomarkers of neuroinflammation (i.e. levels of ROS, nitrite and proinflammatory cytokines TNF and IL-1) and neurodegeneration (assessed histologically). The single injection of colchicine resulted in impaired memory and neurodegeneration (significant presence of plaques, Nissl granule chromatolysis) in various brain areas (frontal cortex, amygdala, parietal cortex, corpus striatum), with maximum severity in the hippocampus. While IL-1, TNF, ROS and nitrite levels were altered in different brain areas in the ICIR rats, these parameters had their greatest change in the hippocampus. This study showed that icv injection of colchicine caused strong neurodegeneration and neuroinflammation in the hippocampus of rats and the increases in neurodegeneration were corroborated with those of neuroinflammation at the site. The present study also showed that the extent of neurodegeneration and neuroinflammation in different brain areas of the colchicine-injected rats were AD-like and supported the fact that such rats might have the ability to serve as a sporadic model of AD.

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Prostaglandin D2 induces programmed cell death in Trypanosoma brucei bloodstream form

Cited by 81 publications

References 64 publications

Sphingolipid synthesis is necessary for kinetoplast segregation and cytokinesis in Trypanosoma brucei

Sphingolipid synthesis is necessary for kinetoplast segregation and cytokinesis in Trypanosoma brucei

Staurosporine-Induced Cell Death in <em>Trypanosoma brucei</em> and the Role of Endonuclease G during Apoptosis

A comparison of neurodegeneration linked with neuroinflammation in different brain areas of rats after intracerebroventricular colchicine injection

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Prostaglandin D2 induces programmed cell death in Trypanosoma brucei bloodstream form

Cited by 81 publications

References 64 publications

Sphingolipid synthesis is necessary for kinetoplast segregation and cytokinesis in Trypanosoma brucei

Sphingolipid synthesis is necessary for kinetoplast segregation and cytokinesis in Trypanosoma brucei

Staurosporine-Induced Cell Death in &lt;em&gt;Trypanosoma brucei&lt;/em&gt; and the Role of Endonuclease G during Apoptosis

A comparison of neurodegeneration linked with neuroinflammation in different brain areas of rats after intracerebroventricular colchicine injection

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Staurosporine-Induced Cell Death in <em>Trypanosoma brucei</em> and the Role of Endonuclease G during Apoptosis