A glaucoma‐ and ALS‐associated mutant of OPTN induces neuronal cell death dependent on Tbk1 activity, autophagy and ER stress

FEBS Journal ◽  
2021 ◽  
Author(s):  
Swetha Medchalmi ◽  
Priyanka Tare ◽  
Zuberwasim Sayyad ◽  
Ghanshyam Swarup
Keyword(s):  
Cell Death ◽  
Er Stress ◽  
Neuronal Cell Death ◽  
Neuronal Cell

scholarly journals Oxidative Damage to the Endoplasmic Reticulum is Implicated in Ischemic Neuronal Cell Death

2003 ◽  
Vol 23 (10) ◽  
pp. 1117-1128 ◽  
Author(s):  
Takeshi Hayashi ◽  
Atsushi Saito ◽  
Shuzo Okuno ◽  
Michel Ferrand-Drake ◽  
Robert L Dodd ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Cell Death ◽  
Er Stress ◽  
Protein Modification ◽  
Neuronal Degeneration ◽  
Neuronal Damage ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Transgenic Animals ◽  
Initiation Factor

The endoplasmic reticulum (ER), which plays important roles in apoptosis, is susceptible to oxidative stress. Because reactive oxygen species (ROS) are robustly produced in the ischemic brain, ER damage by ROS may be implicated in ischemic neuronal cell death. We induced global brain ischemia on wild-type and copper/zinc superoxide dismutase (SOD1) transgenic rats and compared ER stress and neuronal damage. Phosphorylated forms of eukaryotic initiation factor 2α (eIF2α) and RNA-dependent protein kinase-like ER eIF2α kinase (PERK), both of which play active roles in apoptosis, were increased in hippocampal CA1 neurons after ischemia but to a lesser degree in the transgenic animals. This finding, together with the finding that the transgenic animals showed decreased neuronal degeneration, indicates that oxidative ER damage is involved in ischemic neuronal cell death. To elucidate the mechanisms of ER damage by ROS, we analyzed glucose-regulated protein 78 (GRP78) binding with PERK and oxidative ER protein modification. The proteins were oxidatively modified and stagnated in the ER lumen, and GRP78 was detached from PERK by ischemia, all of which were attenuated by SOD1 overexpression. We propose that ROS attack and modify ER proteins and elicit ER stress response, which results in neuronal cell death.

scholarly journals Nickel Enhances Zinc-Induced Neuronal Cell Death by Priming the Endoplasmic Reticulum Stress Response

2019 ◽  
Vol 2019 ◽  
pp. 1-13 ◽  
Author(s):  
Ken-ichiro Tanaka ◽  
Misato Kasai ◽  
Mikako Shimoda ◽  
Ayane Shimizu ◽  
Maho Kubota ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Cell Death ◽  
Stress Response ◽  
Trace Metals ◽  
Er Stress ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Endoplasmic Reticulum Stress Response ◽  
Dependent Manner ◽  
Er Stress Response

Trace metals such as zinc (Zn), copper (Cu), and nickel (Ni) play important roles in various physiological functions such as immunity, cell division, and protein synthesis in a wide variety of species. However, excessive amounts of these trace metals cause disorders in various tissues of the central nervous system, respiratory system, and other vital organs. Our previous analysis focusing on neurotoxicity resulting from interactions between Zn and Cu revealed that Cu2+ markedly enhances Zn2+-induced neuronal cell death by activating oxidative stress and the endoplasmic reticulum (ER) stress response. However, neurotoxicity arising from interactions between zinc and metals other than copper has not been examined. Thus, in the current study, we examined the effect of Ni2+ on Zn2+-induced neurotoxicity. Initially, we found that nontoxic concentrations (0–60 μM) of Ni2+ enhance Zn2+-induced neurotoxicity in an immortalized hypothalamic neuronal cell line (GT1-7) in a dose-dependent manner. Next, we analyzed the mechanism enhancing neuronal cell death, focusing on the ER stress response. Our results revealed that Ni2+ treatment significantly primed the Zn2+-induced ER stress response, especially expression of the CCAAT-enhancer-binding protein homologous protein (CHOP). Finally, we examined the effect of carnosine (an endogenous peptide) on Ni2+/Zn2+-induced neurotoxicity and found that carnosine attenuated Ni2+/Zn2+-induced neuronal cell death and ER stress occurring before cell death. Based on our results, Ni2+ treatment significantly enhances Zn2+-induced neuronal cell death by priming the ER stress response. Thus, compounds that decrease the ER stress response, such as carnosine, may be beneficial for neurological diseases.

scholarly journals Vitamin K2 Modulates Organelle Damage and Tauopathy Induced by Streptozotocin and Menadione in SH-SY5Y Cells

Antioxidants ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 983
Author(s):  
Shruti Shandilya ◽  
Kavindra Kumar Kesari ◽  
Janne Ruokolainen
Keyword(s):  
Cell Death ◽  
Membrane Potential ◽  
Er Stress ◽  
Mitochondrial Membrane Potential ◽  
Tau Protein ◽  
Mitochondrial Membrane ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Vitamin K2 ◽  
Total Tau

Vitamin K2, known for its antioxidative and anti-inflammatory properties, can act as a potent neuroprotective molecule. Despite its action against mitochondrial dysfunction, the mechanism underlying the links between the protective effects of vitamin K2 and endoplasmic reticulum (ER) stress along with basal levels of total tau protein and amyloid-beta 42 (Aβ42) has not been elucidated yet. To understand the neuroprotective effect of vitamin K2 during metabolic complications, SH-SY5Y cells were treated with streptozotocin for 24 h and menadione for 2 h in a dose-dependent manner, followed by post-treatment of vitamin K2 for 5 h. The modulating effects of vitamin K2 on cell viability, lactate dehydrogenase release, reactive oxygen species (ROS), mitochondrial membrane potential, ER stress marker (CHOP), an indicator of unfolded protein response (UPR), inositol requiring enzyme 1 (p-IRE1α), glycogen synthase kinase 3 (GSK3α/β), total tau and Aβ42 were studied. Results showed that vitamin K2 significantly reduces neuronal cell death by inhibiting cytotoxicity and ROS levels and helps in the retainment of mitochondrial membrane potential. Moreover, vitamin K2 significantly decreased the expression of CHOP protein along with the levels and the nuclear localization of p-IRE1 α, thus showing its significant role in inhibiting chronic ER stress-mediated UPR and eventually cell death. In addition, vitamin K2 significantly down-regulated the expression of GSK3 α/β together with the levels of total tau protein, with a petite effect on secreted Aβ42 levels. These results suggested that vitamin K2 alleviated mitochondrial damage, ER stress and tauopathy-mediated neuronal cell death, which highlights its role as new antioxidative therapeutics targeting related cellular processes.

scholarly journals Endoplasmic Reticulum Stress and Parkinson’s Disease: The Role of HRD1 in Averting Apoptosis in Neurodegenerative Disease

2013 ◽  
Vol 2013 ◽  
pp. 1-7 ◽  
Author(s):  
Tomohiro Omura ◽  
Masayuki Kaneko ◽  
Yasunobu Okuma ◽  
Kazuo Matsubara ◽  
Yasuyuki Nomura
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Endoplasmic Reticulum ◽  
Cell Death ◽  
Er Stress ◽  
Neuronal Death ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Causative Factor ◽  
6 Hydroxydopamine

Endoplasmic reticulum (ER) stress has been known to be involved in the pathogenesis of various diseases, particularly neurodegenerative disorders such as Parkinson’s disease (PD). We previously identified the human ubiquitin ligase HRD1 that is associated with protection against ER stress and its associated apoptosis. HRD1 promotes the ubiquitination and degradation of Parkin-associated endothelin receptor-like receptor (Pael-R), an ER stress inducer and causative factor of familial PD, thereby preventing Pael-R-induced neuronal cell death. Moreover, upregulation of HRD1 by the antiepileptic drug zonisamide suppresses 6-hydroxydopamine-induced neuronal cell death. We review recent progress in the studies on the mechanism of ER stress-induced neuronal death related to PD, particularly focusing on the involvement of HRD1 in the prevention of neuronal death as well as a potential therapeutic approach for PD based on the upregulation of HRD1.

Neuropeptide Y mitigates ER stress–induced neuronal cell death by activating the PI3K–XBP1 pathway

2018 ◽  
Vol 97 (5) ◽  
pp. 339-348 ◽  
Author(s):  
Do Yeon Lee ◽  
Seung Hyun Hong ◽  
Bokyung Kim ◽  
Dong-Seok Lee ◽  
Kweon Yu ◽  
...  
Keyword(s):  
Cell Death ◽  
Er Stress ◽  
Neuropeptide Y ◽  
Neuronal Cell Death ◽  
Neuronal Cell

scholarly journals Disrupted autophagy after spinal cord injury is associated with ER stress and neuronal cell death

2015 ◽  
Vol 6 (1) ◽  
pp. e1582-e1582 ◽  
Author(s):  
S Liu ◽  
C Sarkar ◽  
M Dinizo ◽  
A I Faden ◽  
E Y Koh ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Cell Death ◽  
Er Stress ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Cord Injury

scholarly journals Neuroprotective Role of Akt in Hypoxia Adaptation in Andeans

2021 ◽  
Vol 14 ◽  
Author(s):  
Helen Zhao ◽  
Jonathan Lin ◽  
Gary Sieck ◽  
Gabriel G. Haddad
Keyword(s):  
Cell Death ◽  
Er Stress ◽  
Mitochondrial Dynamics ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Cellular Mechanisms ◽  
Akt Activation ◽  
Stress Markers ◽  
Hypoxia Adaptation ◽  
Stress Related Genes

Chronic mountain sickness (CMS) is a disease that potentially threatens a large segment of high-altitude populations during extended living at altitudes above 2,500 m. Patients with CMS suffer from severe hypoxemia, excessive erythrocytosis and neurologic deficits. The cellular mechanisms underlying CMS neuropathology remain unknown. We previously showed that iPSC-derived CMS neurons have altered mitochondrial dynamics and increased susceptibility to hypoxia-induced cell death. Genome analysis from the same population identified many ER stress-related genes that play an important role in hypoxia adaptation or lack thereof. In the current study, we showed that iPSC-derived CMS neurons have increased expression of ER stress markers Grp78 and XBP1s under normoxia and hyperphosphorylation of PERK under hypoxia, alleviating ER stress does not rescue the hypoxia-induced CMS neuronal cell death. Akt is a cytosolic regulator of ER stress with PERK as a direct target of Akt. CMS neurons exhibited lack of Akt activation and lack of increased Parkin expression as compared to non-CMS neurons under hypoxia. By enhancing Akt activation and Parkin overexpression, hypoxia-induced CMS neuronal cell death was reduced. Taken together, we propose that increased Akt activation protects non-CMS from hypoxia-induced cell death. In contrast, impaired adaptive mechanisms including failure to activate Akt and increase Parkin expression render CMS neurons more susceptible to hypoxia-induced cell death.

scholarly journals Damage to the Endoplasmic Reticulum and Activation of Apoptotic Machinery by Oxidative Stress in Ischemic Neurons

2005 ◽  
Vol 25 (1) ◽  
pp. 41-53 ◽  
Author(s):  
Takeshi Hayashi ◽  
Atsushi Saito ◽  
Shuzo Okuno ◽  
Michel Ferrand-Drake ◽  
Robert L Dodd ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Endoplasmic Reticulum ◽  
Cell Death ◽  
Er Stress ◽  
Neuronal Degeneration ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Wild Type ◽  
Transgenic Rats ◽  
The Brain

The endoplasmic reticulum (ER), which plays a role in apoptosis, is susceptible to oxidative stress. Because superoxide is produced in the brain after ischemia/reperfusion, oxidative injury to this organelle may be implicated in ischemic neuronal cell death. Activating transcription factor-4 (ATF-4) and C/EBP-homologous protein (CHOP), both of which are involved in apoptosis, are induced by severe ER stress. Using wild-type and human copper/zinc superoxide dismutase transgenic rats, we observed induction of these molecules in the brain after global cerebral ischemia and compared them with neuronal degeneration. In ischemic, wild-type brains, expression of ATF-4 and CHOP was increased in the hippocampal CA1 neurons that would later undergo apoptosis. Transgenic rats had a mild increase in ATF-4 and CHOP and minimal neuronal degeneration, indicating that superoxide was involved in ER stress-induced cell death. We further confirmed attenuation on induction of these molecules in transgenic mouse brains after focal ischemia. When superoxide was visualized with ethidium, signals for ATF-4 and superoxide overlapped in the same cells. Moreover, lipids in the ER were robustly peroxidized by ischemia but were attenuated in transgenic animals. This indicates that superoxide attacked and damaged the ER, and that oxidative ER damage is implicated in ischemic neuronal cell death.

scholarly journals Betulin Protects HT-22 Hippocampal Cells against ER Stress through Induction of Heme Oxygenase-1 and Inhibition of ROS Production

2019 ◽  
Vol 14 (12) ◽  
pp. 1934578X1989668 ◽  
Author(s):  
Phil Jun Lee ◽  
Hye-Jin Park ◽  
Hee Min Yoo ◽  
Namki Cho
Keyword(s):  
Cell Death ◽  
Neurodegenerative Diseases ◽  
Er Stress ◽  
Heme Oxygenase ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Ros Generation ◽  
Heme Oxygenase 1 ◽  
Ros Scavenging ◽  
Neuroprotective Effects

A key pathologic event in neurodegenerative diseases, such as Alzheimer’s disease and Parkinson’s disease, is endoplasmic reticulum (ER) stress-induced neuronal cell death. ER stress-induced generation of reactive oxygen species (ROS) has been implicated in neurological disease processes. Betulin is one of the major triterpenoids found in Betula platyphylla that possesses several biological properties, including cytoprotective and antioxidative effects. Therefore, we investigated whether betulin could prevent ER stress-induced neurotoxicity in HT-22 hippocampal neuronal cells. We observed that betulin reduced the thapsigargin (TG, an ER stress inducer)-induced apoptosis of HT-22 cells. Moreover, the cytoprotective effects of betulin were comparable to those of tauroursodeoxycholic acid, a potent ER stress-reducing agent. In our study, we confirmed that the ER stress-induced accumulation of ROS plays an important role in HT-22 cell death. Betulin also displayed cytoprotective effects in TG-injured HT-22 cells by reducing ROS generation; these results were comparable to those for N-acetyl-L-cysteine, a known ROS inhibitor. In addition, SnPP, a heme oxygenase-1 (HO-1) inhibitor significantly blocked the cytoprotective effects and ROS scavenging activity of betulin. Based on these results, we believe that betulin-mediated induction of HO-1 may contribute to the neuroprotective effects against ER stress in HT-22 hippocampal cells. We also found that betulin significantly inhibited the TG-induced expression of CHOP and caspase-12. These results demonstrated that betulin could serve as a potential therapeutic agent against ER stress-induced neurodegenerative diseases.

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