bims-ershed Biomed News
on ER Stress in Health and Diseases
Issue of 2021‒04‒25
twelve papers selected by
Matías Eduardo González Quiroz
Worker’s Hospital

  1. J Neurochem. 2021 Apr 19.
      The endoplasmic reticulum (ER)-localized Sigma-1 receptor (S1R) is neuroprotective in models of neurodegenerative diseases, among them Huntington disease (HD). Recent clinical trials in HD patients and preclinical studies in cellular and mouse HD models suggest a therapeutic potential for the high-affinity S1R agonist pridopidine. However, the molecular mechanisms of the cytoprotective effect are unclear. We have previously reported strong induction of ER stress by toxic mutant huntingtin (mHtt) oligomers, which is reduced upon sequestration of these mHtt oligomers into large aggregates. Here, we show that pridopidine significantly ameliorates mHtt-induced ER stress in cellular HD models, starting at low nanomolar concentrations. Pridopidine reduced the levels of markers of the three branches of the unfolded protein response (UPR), showing the strongest effects on the PKR-like endoplasmic reticulum kinase (PERK) branch. The effect is S1R-dependent, as it is abolished in cells expressing mHtt in which the S1R was deleted using CRISPR/Cas9 technology. mHtt increased the level of the detergent-insoluble fraction of S1R, suggesting a compensatory cellular mechanism that responds to increased ER stress. Pridopidine further enhanced levels of insoluble S1R, suggesting the stabilization of activated S1R oligomers. These S1R oligomeric species appeared in ER-localized patches, and not in the mitochondria-associated membranes nor the ER-derived quality control compartment. The colocalization of S1R with the chaperone BiP was significantly reduced by mHtt, and pridopidine restored this colocalization to normal, unstressed levels. Pridopidine increased toxic oligomeric mHtt recruitment into less toxic large SDS-insoluble aggregates, suggesting that this in turn reduces ER stress and cytotoxicity.
    Keywords:  ER stress; Huntington disease; Sigma-1 receptor; neurodegeneration; unfolded protein response
  2. Front Cell Neurosci. 2021 ;15 653688
      Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease of the motor system with complex determinants, including genetic and non-genetic factors. Despite this heterogeneity, a key pathological signature is the mislocalization and aggregation of specific proteins in the cytoplasm, suggesting that convergent pathogenic mechanisms focusing on disturbances in proteostasis are important in ALS. In addition, many cellular processes have been identified as potentially contributing to disease initiation and progression, such as defects in axonal transport, autophagy, nucleocytoplasmic transport, ER stress, calcium metabolism, the unfolded protein response and mitochondrial function. Here we review the evidence from in vitro and in vivo models of C9ORF72 and TDP-43-related ALS supporting a central role in pathogenesis for endoplasmic reticulum stress, which activates an unfolded protein response (UPR), and mitochondrial dysfunction. Disruption in the finely tuned signaling between the ER and mitochondria through calcium ions may be a crucial trigger of mitochondrial deficits and initiate an apoptotic signaling cascade, thus acting as a point of convergence for multiple upstream disturbances of cellular homeostasis and constituting a potentially important therapeutic target.
    Keywords:  ALS; C9orf72; TDP-43; UPR; calcium homeostasis; endoplasmic reticulum; mitochondria
  3. J Neurosci. 2021 Apr 20. pii: JN-RM-2384-20. [Epub ahead of print]
      Schwann cells produce a considerable amount of lipids and proteins to form myelin in the peripheral nervous system (PNS). For this reason, the quality control of myelin proteins is crucial to ensure proper myelin synthesis. Deletion of serine 63 from P0 (P0S63del) protein in myelin forming Schwann cells causes Charcot-Marie-Tooth type 1B (CMT1B) neuropathy in humans and mice. Misfolded P0S63del accumulates in the endoplasmic reticulum (ER) of Schwann cells where it elicits the unfolded protein response (UPR). PERK is the UPR transducer that attenuates global translation and reduces ER stress by phosphorylating the translation initiation factor eIF2alpha. Paradoxically, Perk ablation in P0S63del Schwann cells (S63del/PerkSCKO ) reduced the level of P-eIF2alpha, leaving UPR markers upregulated, yet unexpectedly improved S63del myelin defects in vivo We therefore investigated the hypothesis that PERK may interfere with signals outside of the UPR and specifically with Calcineurin/NFATc4 pro-myelinating pathway. Using mouse genetics including females and males in our experimental setting, we show that PERK and Calcineurin interact in P0S63del nerves and that Calcineurin activity and NFATc4 nuclear localization are increased in S63del Schwann cells, without altering EGR2/KROX20 expression. Moreover, genetic manipulation of the Calcineurin subunits appears to be either protective or toxic in S63del in a context dependent manner, suggesting that Schwann cells are highly sensitive to alterations of Calcineurin activity.SIGNIFICANCE STATEMENT:Our work shows a novel activity and function for Calcineurin in Schwann cells in the context of ER stress. Schwann cells expressing the S63del mutation in P0 protein induce the unfolded protein response and upregulate Calcineurin activity. Calcineurin interacts with the ER stress transducer PERK but the relationship between the UPR and Calcineurin in Schwann cells is unclear. Here we propose a protective role for Calcineurin in S63del neuropathy although Schwann cells appear to be very sensitive to its regulation. The paper uncovers a new important role for Calcineurin in a demyelinating diseases.
  4. Prog Biophys Mol Biol. 2021 Apr 20. pii: S0079-6107(21)00030-4. [Epub ahead of print]
      The maintenance of genome integrity is critical for the faithful replication of the genome during cell division and for protecting cells from accumulation of DNA damage, which if left unrepaired leads to a loss of genetic information, a breakdown in cell function and ultimately cell death and cancer. ATM and ATR are master kinases that are integral to homologous recombination-mediated repair of double strand breaks and preventing accumulation of dangerous DNA structures and genome instability during replication stress. While the roles of ATM and ATR are heavily intertwined in response to double strand breaks, their roles diverge in the response to replication stress. This review summarises our understanding of the players and their mode of actions in recruitment, activation and activity of ATM and ATR in response to DNA damage and replication stress and discusses how controlling localisation of these kinases and their activators allows them to orchestrate a stress-specific response.
    Keywords:  DNA damage Signalling; Homologous recombination; PIKKs; Protein kinases; Regulation; Replication stress
  5. Oncology (Williston Park). 2021 Apr 21. 35(4): 190-198
      Messenger RNA (mRNA) vaccines are a relatively new class of vaccines. They combine the potential of mRNA to encode for almost any protein with an excellent safety profile and a flexible production process. During the last decade, the mRNA vaccine approach has been increasingly recognized and viewed as a versatile tool for the development of new innovative therapeutics not only in infectious disease settings but also in cancer. mRNA vaccines traditionally consist of a messenger RNA synthesized by in vitro transcription using a bacteriophage RNA polymerase and a template DNA that encodes the antigen(s) of interest. Once administered and internalized by host cells, the mRNA transcripts are translated directly in the cytoplasm of the cell. The resulting antigens are presented to the immune system cells to stimulate an immune response. Dendritic cells (DCs) can be utilized as a carrier by delivering tumor-associated antigen mRNAs or total tumor RNA to their cytoplasm; then, the mRNA-loaded DCs can be delivered to the host to elicit a specific immune response. Recently, 2 mRNA vaccines were approved for the first time for human use-to prevent COVID-19 infection-bringing excitement for the future possibilities of this approach for cancer immunotherapy as well as for preventing other infectious diseases.
  6. Cell Discov. 2020 Apr 21. 6(1): 21
      In response to DNA damage, p53-mediated signaling is regulated by protein phosphorylation and ubiquitination to precisely control G2 checkpoint. Here we demonstrated that protein SUMOylation also engaged in regulation of p53-mediated G2 checkpoint. We found that G2 DNA damage suppressed SENP3 phosphorylation at G2/M phases in p53-dependent manner. We further found that the suppression of SENP3 phosphorylation was crucial for efficient DNA damage/p53-induced G2 checkpoint and G2 arrest. Mechanistically, we identified Cdh1, a subunit of APC/C complex, was a SUMOylated protein at G2/M phase. SENP3 could de-SUMOylate Cdh1. DNA damage/p53-induced suppression of SENP3 phosphorylation activated SENP3 de-SUMOylation of Cdh. De-SUMOylation promoted Cdh1 de-phosphorylation by phosphatase Cdc14B, and then activated APC/CCdh1 E3 ligase activity to ubiquitate and degrade Polo-like kinase 1 (Plk1) in process of G2 checkpoint. These data reveal that p53-mediated inhibition of SENP3 phosphorylation regulates the activation of Cdc14b-APC/CCdh1-Plk1 axis to control DNA damage-induced G2 checkpoint.
  7. Toxicol Res (Camb). 2021 Mar;10(2): 284-291
      Cigarette smoking is one of the major causes of coronary artery disease (CAD) as is diabetes. However, nicotine has been generally regarded as safe and is used in smoking cessation programs. This presumption of nicotine safety was examined in human coronary artery endothelial cells (HCAEC). Endoplasmic reticulum (ER) stress was measured using the secreted alkaline phosphatase (SAP) assay. The ER stress markers inositol-requiring enzyme 1α (IRE1α), phospho-IRE1α, double-stranded RNA-activated protein kinase-like endoplasmic reticulum kinase (PERK), phospho-PERK, activating transcription factor 6 (ATF6), and glucose-related protein 78 (GRP78) were measured by western blot. Cell viability was measured using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and crystal violet staining. Intact and cleaved caspase 3, BH3 interacting-domain death agonist (BID), and B-cell lymphoma 2 (Bcl2) were measured by western blot. In cells transfected with the SAP expression plasmid, treatment with nicotine resulted in a dose-dependent decrease in SAP expression with no noticeable toxicity. Nicotine (10 nM) also increased IRE1α and PERK phosphorylation, and ATF6 and GRP78 expression. Although nicotine at concentrations up to 10 μM did not cause cell death, treatment of HCAEC with 10 nM nicotine in the presence of 13.8 mM dextrose aggravated ER stress, increased cell death, increased cleaved caspase 3 and BID, and decreased BCL2. Nicotine at concentrations commonly achieved in nicotine-replacement therapy (NRT) significantly increased ER stress in HCAEC and aggravated dextrose-induced ER stress and cell apoptosis. People using electronic cigarettes and on NRT may be at increased risk for CAD.
    Keywords:  ER stress; HCAEC; apoptosis; nicotine
  8. Nature. 2021 Apr 23.
    Keywords:  Careers; Ethics; Philosophy
  9. Nature. 2021 Apr 19.
    Keywords:  Genetics; Immunology; Medical research
  10. Genes Immun. 2021 Apr 19.
      The microbiome plays a fundamental role in the maturation, function, and regulation of the host-immune system from birth to old age. In return, the immune system has co-evolved a mutualistic relationship with trillions of beneficial microbes residing our bodies while mounting efficient responses to fight invading pathogens. As we age, both the immune system and the gut microbiome undergo significant changes in composition and function that correlate with increased susceptibility to infectious diseases and reduced vaccination responses. Emerging studies suggest that targeting age-related dysbiosis can improve health- and lifespan, in part through reducing systemic low-grade inflammation and immunosenescence-two hallmarks of the aging process. However-a cause and effect relationship of age-related dysbiosis and associated functional declines in immune cell functioning have yet to be demonstrated in clinical settings. This review aims to (i) give an overview on hallmarks of the aging immune system and gut microbiome, (ii) discuss the impact of age-related changes in the gut commensal community structure (introduced as microb-aging) on host-immune fitness and health, and (iii) summarize prebiotic- and probiotic clinical intervention trials aiming to reinforce age-related declines in immune cell functioning through microbiome modulation or rejuvenation.
  11. EXCLI J. 2021 ;20 614-624
      Glioblastoma multiforme is a malignant neoplasm of the brain with poor prognosis. The first-line drug against glioblastoma is the alkylating agent temozolamide (TMZ); unfortunately, treatment resistance and tumor re-incidence are common. In some cases, immunogenic cell death (ICD) inducers can decrease treatment resistance and tumor recurrence by stimulating an antitumor specific immune response. Not all ICD inducers, however, are suitable for glioma patients because of the low permeability of the blood-brain barrier (BBB). Panobinostat (PAN), a histone deacetylase inhibitor and Lophophora williamsii (LW) extract can pass through the BBB and have antitumor properties. The aim of this study is to evaluate the cytotoxic potential of TMZ, PAN and LW extract against the glioma C6 cell line, and its role in the release of damage-associated molecular patterns (DAMPs), which is a hallmark of ICD. Our results indicate that all treatments induce cellular death in a time- and concentration-dependent manner, and that PAN and LW extract induce apoptosis, whereas TMZ induces apoptosis and necrosis. Also, that some of the treatments and their sequential administration induce the release of DAMPs. Furthermore, in a rat glioma model, we observed that all treatments decreased tumor volume, but the in vivo cell death mechanism was not ICD. Our findings indicate that TMZ, PAN, and LW combination have a cytotoxic effect against glioma cells but do not induce ICD.
    Keywords:  DAMPs; Lophophora williamsii; glioblastoma; immunogenic cell death; panobinostat; temozolamide
  12. Nature. 2021 Apr 21.
    Keywords:  Public health; Virology