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.

scholarly journals Pneumolysin Causes Neuronal Cell Death through Mitochondrial Damage

2007 ◽  
Vol 75 (9) ◽  
pp. 4245-4254 ◽  
Author(s):  
Johann S. Braun ◽  
Olaf Hoffmann ◽  
Miriam Schickhaus ◽  
Dorette Freyer ◽  
Emilie Dagand ◽  
...  
Keyword(s):  
Cell Death ◽  
Caspase 3 ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Mitochondrial Damage ◽  
Cell Death Pathways ◽  
Apoptosis Protein ◽  
Mitochondrial Toxin ◽  
Induced Apoptosis ◽  
Apoptosis Inducing Factor

ABSTRACT Bacterial toxins such as pneumolysin are key mediators of cytotoxicity in infections. Pneumolysin is a pore-forming toxin released by Streptococcus pneumoniae, the major cause of bacterial meningitis. We found that pneumolysin is the pneumococcal factor that accounts for the cell death pathways induced by live bacteria in primary neurons. The pore-forming activity of pneumolysin is essential for the induction of mitochondrial damage and apoptosis. Pneumolysin colocalized with mitochondrial membranes, altered the mitochondrial membrane potential, and caused the release of apoptosis-inducing factor and cell death. Pneumolysin induced neuronal apoptosis without activating caspase-1, -3, or -8. Wild-type pneumococci also induced apoptosis without activation of caspase-3, whereas pneumolysin-negative pneumococci activated caspase-3 through the release of bacterial hydrogen peroxide. Pneumolysin caused upregulation of X-chromosome-linked inhibitor of apoptosis protein and inhibited staurosporine-induced caspase activation, suggesting the presence of actively suppressive mechanisms on caspases. In conclusion, our results indicate additional functions of pneumolysin as a mitochondrial toxin and as a determinant of caspase-independent apoptosis. Considering this, blocking of pneumolysin may be a promising cytoprotective strategy in pneumococcal meningitis and other infections.

scholarly journals AC-YVAD-CMK Inhibits Pyroptosis and Improves Functional Outcome after Intracerebral Hemorrhage

2018 ◽  
Vol 2018 ◽  
pp. 1-10 ◽  
Author(s):  
Xiao Lin ◽  
Haotuo Ye ◽  
Felix Siaw-Debrah ◽  
Sishi Pan ◽  
Zibin He ◽  
...  
Keyword(s):  
Cell Death ◽  
Intracerebral Hemorrhage ◽  
Cell Damage ◽  
Neuronal Cell ◽  
Neurological Function ◽  
Inflammatory Factors ◽  
Neuroprotective Effects ◽  
Caspase 1 ◽  
Cell Death Pathways ◽  
Cell Death Pathway

Intracerebral hemorrhage (ICH) refers to bleeding in the brain and is associated with the release of large amount of inflammasomes, and the activation of different cell death pathways. These cell death pathways lead to removal of inactivated and damaged cells and also result in neuronal cell damage. Pyroptosis is a newly discovered cell death pathway that has gained attention in recent years. This pathway mainly depends on activation of caspase-1-mediated cascades to cause cell death. We tested a well-known selective inhibitor of caspase-1, AC-YVAD-CMK, which has previously been found to have neuroprotective effects in ICH mice model, to ascertain its effects on the activation of inflammasomes mediated pyroptosis. Our results showed that AC-YVAD-CMK could reduce caspase-1 activation and inhibit IL-1β production and maturation, but has no effect on NLRP3 expression, an upstream inflammatory complex. AC-YVAD-CMK administration also resulted in reduction in M1-type microglia polarization around the hematoma, while increasing the number of M2-type cells. Furthermore, AC-YVAD-CMK treated mice showed some recovery of neurological function after hemorrhage especially at the hyperacute and subacute stage resulting in some degree of limb movement. In conclusion, we are of the view that AC-YVAD-CMK could inhibit pyroptosis, decrease the secretion or activation of inflammatory factors, and affect the polarization of microglia resulting in improvement of neurological function after ICH.

scholarly journals Hericium Erinaceus Prevents DEHP-Induced Mitochondrial Dysfunction and Apoptosis in PC12 Cells

2020 ◽  
Vol 21 (6) ◽  
pp. 2138 ◽  
Author(s):  
Ines Amara ◽  
Maria Scuto ◽  
Agata Zappalà ◽  
Maria Laura Ontario ◽  
Antonio Petralia ◽  
...  
Keyword(s):  
Cell Death ◽  
Protective Effect ◽  
Pc12 Cells ◽  
Antioxidant Activities ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Hericium Erinaceus ◽  
Nutritional Strategy ◽  
Induced Apoptosis ◽  
Ethylhexyl Phthalate

Hericium Erinaceus (HE) is a medicinal plant known to possess anticarcinogenic, antibiotic, and antioxidant activities. It has been shown to have a protective effect against ischemia-injury-induced neuronal cell death in rats. As an extending study, here we examined in pheochromocytoma 12 (PC12) cells, whether HE could exert a protective effect against oxidative stress and apoptosis induced by di(2-ethylhexyl)phthalate (DEHP), a plasticizer known to cause neurotoxicity. We demonstrated that pretreatment with HE significantly attenuated DEHP induced cell death. This protective effect may be attributed to its ability to reduce intracellular reactive oxygen species levels, preserving the activity of respiratory complexes and stabilizing the mitochondrial membrane potential. Additionally, HE pretreatment significantly modulated Nrf2 and Nrf2-dependent vitagenes expression, preventing the increase of pro-apoptotic and the decrease of anti-apoptotic markers. Collectively, our data provide evidence of new preventive nutritional strategy using HE against DEHP-induced apoptosis in PC12 cells.

Lipocalin-type prostaglandin D synthase protects against oxidative stress-induced neuronal cell death

2012 ◽  
Vol 443 (1) ◽  
pp. 75-84 ◽  
Author(s):  
Ayano Fukuhara ◽  
Mao Yamada ◽  
Ko Fujimori ◽  
Yuya Miyamoto ◽  
Toshihide Kusumoto ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cell Death ◽  
Neuroblastoma Cell ◽  
Neuronal Cells ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Dependent Manner ◽  
Functional Protein ◽  
Prostaglandin D Synthase ◽  
Induced Apoptosis

L-PGDS [lipocalin-type PGD (prostaglandin D) synthase] is a dual-functional protein, acting as a PGD2-producing enzyme and a lipid transporter. L-PGDS is a member of the lipocalin superfamily and can bind a wide variety of lipophilic molecules. In the present study we demonstrate the protective effect of L-PGDS on H2O2-induced apoptosis in neuroblastoma cell line SH-SY5Y. L-PGDS expression was increased in H2O2-treated neuronal cells, and the L-PGDS level was highly associated with H2O2-induced apoptosis, indicating that L-PGDS protected the neuronal cells against H2O2-mediated cell death. A cell viability assay revealed that L-PGDS protected against H2O2-induced cell death in a concentration-dependent manner. Furthermore, the titration of free thiols in H2O2-treated L-PGDS revealed that H2O2 reacted with the thiol of Cys65 of L-PGDS. The MALDI–TOF (matrix-assisted laser-desorption ionization–time-of-flight)-MS spectrum of H2O2-treated L-PGDS showed a 32 Da increase in the mass relative to that of the untreated protein, showing that the thiol was oxidized to sulfinic acid. The binding affinities of oxidized L-PGDS for lipophilic molecules were comparable with those of untreated L-PGDS. Taken together, these results demonstrate that L-PGDS protected against neuronal cell death by scavenging reactive oxygen species without losing its ligand-binding function. The novel function of L-PGDS could be useful for the suppression of oxidative stress-mediated neurodegenerative diseases.

scholarly journals Protection of neuronal cell death against diabetes-induced apoptosis by Fas blocker ZB4

2014 ◽  
Vol 42 (4) ◽  
pp. 949-957 ◽  
Author(s):  
Fawzia Al Rouq ◽  
Durdana Hammad ◽  
Sultan Ayoub Meo
Keyword(s):  
Cell Death ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Induced Apoptosis

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.

Sign in / Sign up

Export Citation Format

Share Document