scholarly journals Increased Nuclear Apoptosis-Inducing Factor after Transient Focal Ischemia: A 12/15-Lipoxygenase-dependent Organelle Damage Pathway

2010 ◽  
Vol 30 (6) ◽  
pp. 1157-1167 ◽  
Author(s):  
Stefanie Pallast ◽  
Ken Arai ◽  
Anton Pekcec ◽  
Kazim Yigitkanli ◽  
Zhanyang Yu ◽  
...  
Keyword(s):  
Cell Death ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Artery Occlusion ◽  
Glutathione Depletion ◽  
Established Cell Line ◽  
Edema Formation ◽  
Cell Death Pathway ◽  
Nuclear Apoptosis ◽  
Apoptosis Inducing Factor

12/15-lipoxygenase (12/15-LOX) contributes to acute neuronal injury and edema formation in mouse models of middle cerebral artery occlusion (MCAO). The apoptosis-inducing factor (AIF) is implicated in caspase-independent forms of apoptosis, and has been linked to ischemic neuronal cell death. We show here that increased AIF in the peri-ischemic cortex of mouse colocalizes with 12/15-LOX after 2 h of MCAO. The 12/15-LOX inhibitor baicalein prevents the increase and nuclear localization of AIF, suggesting this pathway may be partially responsible for the neuroprotective qualities of baicalein. Using an established cell line model of neuronal oxidative stress, we show that 12/15-LOX activated after glutathione depletion leads to AIF translocation to the nucleus, which is abrogated by the 12/15-LOX inhibitor baicalein (control: 19.3%±6.8% versus Glutamate: 64.0%±8.2% versus glutamate plus baicalein: 11.4%±2.2%). Concomitantly, resident proteins of the ER are dispersed throughout the cell (control: 31.0%±8.4% versus glutamate: 70.0%±5.5% versus glutamate plus baicalein: 8.0%±2.7%), suggesting cell death through organelle damage. Taken together, these findings show that 12/15-LOX and AIF are sequential actors in a common cell death pathway that may contribute to stroke-induced brain damage.

scholarly journals Cerebral Ischemia Causes Dysregulation of Synaptic Adhesion in Mouse Synaptosomes

2007 ◽  
Vol 28 (1) ◽  
pp. 99-110 ◽  
Author(s):  
Willard J Costain ◽  
Ingrid Rasquinha ◽  
Jagdeep K Sandhu ◽  
Peter Rippstein ◽  
Bogdan Zurakowski ◽  
...  
Keyword(s):  
Cell Death ◽  
Cerebral Ischemia ◽  
Adhesion Molecules ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Artery Occlusion ◽  
Synaptic Proteins ◽  
Mrna Levels ◽  
Neuronal Nuclei ◽  
Protein Levels

Synaptic pathology is observed during hypoxic events in the central nervous system in the form of altered dendrite structure and conductance changes. These alterations are rapidly reversible, on the return of normoxia, but are thought to initiate subsequent neuronal cell death. To characterize the effects of hypoxia on regulators of synaptic stability, we examined the temporal expression of cell adhesion molecules (CAMs) in synaptosomes after transient middle cerebral artery occlusion (MCAO) in mice. We focused on events preceding the onset of ischemic neuronal cell death (< 48 h). Synaptosome preparations were enriched in synaptically localized proteins and were free of endoplasmic reticulum and nuclear contamination. Electron microscopy showed that the synaptosome preparation was enriched in spheres (≈650 nm in diameter) containing secretory vesicles and postsynaptic densities. Forebrain mRNA levels of synaptically located CAMs was unaffected at 3 h after MCAO. This is contrasted by the observation of consistent downregulation of synaptic CAMs at 20 h after MCAO. Examination of synaptosomal CAM protein content indicated that certain adhesion molecules were decreased as early as 3 h after MCAO. For comparison, synaptosomal Agrn protein levels were unaffected by cerebral ischemia. Furthermore, a marked increase in the levels of p-Ctnnb1 in ischemic synaptosomes was observed. p-Ctnnb1 was detected in hippocampal fiber tracts and in cornu ammonis 1 neuronal nuclei. These results indicate that ischemia induces a dysregulation of a subset of synaptic proteins that are important regulators of synaptic plasticity before the onset of ischemic neuronal cell death.

scholarly journals Augmentation of poly(ADP-ribose) polymerase-dependent neuronal cell death by acidosis

2016 ◽  
Vol 37 (6) ◽  
pp. 1982-1993 ◽  
Author(s):  
Jian Zhang ◽  
Xiaoling Li ◽  
Herman Kwansa ◽  
Yun Tai Kim ◽  
Liye Yi ◽  
...  
Keyword(s):  
Cell Death ◽  
Ion Channel ◽  
Focal Cerebral Ischemia ◽  
Infarct Volume ◽  
Neuronal Cell ◽  
Neuronal Cultures ◽  
Primary Neuronal Cultures ◽  
Tissue Acidosis ◽  
Nuclear Apoptosis ◽  
Apoptosis Inducing Factor

Tissue acidosis is a key component of cerebral ischemic injury, but its influence on cell death signaling pathways is not well defined. One such pathway is parthanatos, in which oxidative damage to DNA results in activation of poly(ADP-ribose) polymerase and generation of poly(ADP-ribose) polymers that trigger release of mitochondrial apoptosis-inducing factor. In primary neuronal cultures, we first investigated whether acidosis per sé is capable of augmenting parthanatos signaling initiated pharmacologically with the DNA alkylating agent, N-methyl- N′-nitro- N-nitrosoguanidine. Exposure of neurons to medium at pH 6.2 for 4 h after N-methyl- N′-nitro- N-nitrosoguanidine washout increased intracellular calcium and augmented the N-methyl- N′-nitro- N-nitrosoguanidine-evoked increase in poly(ADP-ribose) polymers, nuclear apoptosis-inducing factor , and cell death. The augmented nuclear apoptosis-inducing factor and cell death were blocked by the acid-sensitive ion channel-1a inhibitor, psalmotoxin. In vivo, acute hyperglycemia during transient focal cerebral ischemia augmented tissue acidosis, poly(ADP-ribose) polymers formation, and nuclear apoptosis-inducing factor , which was attenuated by a poly(ADP-ribose) polymerase inhibitor. Infarct volume from hyperglycemic ischemia was decreased in poly(ADP-ribose) polymerase 1-null mice. Collectively, these results demonstrate that acidosis can directly amplify neuronal parthanatos in the absence of ischemia through acid-sensitive ion channel-1a . The results further support parthanatos as one of the mechanisms by which ischemia-associated tissue acidosis augments cell death.

scholarly journals Poly (ADP-ribose) polymerase-1 initiated neuronal cell death pathway—do androgens matter?

Neuroscience ◽  
2010 ◽  
Vol 166 (2) ◽  
pp. 476-481 ◽  
Author(s):  
K. Vagnerova ◽  
K. Liu ◽  
A. Ardeshiri ◽  
J. Cheng ◽  
S.J. Murphy ◽  
...  
Keyword(s):  
Cell Death ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Cell Death Pathway

scholarly journals Characterization of Puma-Dependent and Puma-Independent Neuronal Cell Death Pathways following Prolonged Proteasomal Inhibition

2010 ◽  
Vol 30 (23) ◽  
pp. 5484-5501 ◽  
Author(s):  
Liam P. Tuffy ◽  
Caoimhín G. Concannon ◽  
Beatrice D'Orsi ◽  
Matthew A. King ◽  
Ina Woods ◽  
...  
Keyword(s):  
Cell Death ◽  
Proteasome Inhibitor ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Nuclear Condensation ◽  
Apoptosis Pathway ◽  
Mitochondrial Apoptosis Pathway ◽  
Cell Death Pathways ◽  
Cell Death Pathway ◽  
Induced Apoptosis

ABSTRACT Proteasomal stress and the accumulation of polyubiquitinated proteins are key features of numerous neurodegenerative disorders. Previously we demonstrated that stabilization of p53 and activation of its target gene, puma (p53-upregulated mediator of apoptosis), mediated proteasome inhibitor-induced apoptosis in cancer cells. Here we demonstrated that Puma also contributed to proteasome inhibitor-induced apoptosis in mouse neocortical neurons. Although protection afforded by puma gene deletion was incomplete, we found little evidence indicating contributions from other proapoptotic BH3-only proteins. Attenuation of bax expression did not further reduce Puma-independent apoptosis, suggesting that pathways other than the mitochondrial apoptosis pathway were activated. Real-time imaging experiments in wild-type and puma-deficient neurons using a fluorescence resonance energy transfer (FRET)-based caspase sensor confirmed the involvement of a second cell death pathway characterized by caspase activation prior to mitochondrial permeabilization and, more prominently, a third, caspase-independent and Puma-independent pathway characterized by rapid cell shrinkage and nuclear condensation. This pathway involved lysosomal permeabilization in the absence of autophagy activation and was sensitive to cathepsin but not autophagy inhibition. Our data demonstrate that proteasomal stress activates distinct cell death pathways in neurons, leading to both caspase-dependent and caspase-independent apoptosis, and demonstrate independent roles for Puma and lysosomal permeabilization in this model.

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