Cell Stress & Chaperones最新文献

{"title":"Involvement of oxidative stress-AMPK-Cx43-NLRP3 pathway in extracellular matrix remodeling of gastric smooth muscle cells in rats with diabetic gastroparesis","authors":"Baihui Song ,&nbsp;Gaoyuan Zhang ,&nbsp;Yitegele Bao ,&nbsp;Mohan Zhang","doi":"10.1016/j.cstres.2024.04.005","DOIUrl":"10.1016/j.cstres.2024.04.005","url":null,"abstract":"<div><p>This study aimed to investigate the changes in oxidative stress, adenosine monophosphate-activated protein kinase (AMPK), connexin43 (Cx43), nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) expression, and extracellular matrix (ECM) in the gastric smooth muscle tissues of rats with diabetic gastroparesis (DGP) and high glucose-cultured gastric smooth muscle cells, determine the existence of oxidative stress-AMPK-Cx43-NLRP3 pathway under high glucose condition, and the involvement of this pathway in ECM remodeling in DGP rats. The results showed that with increasing duration of diabetes, oxidation stress levels gradually increased, the AMPK activity decreased first and then increased, NLRP3, CX43 expression, and membrane/cytoplasm ratio of Cx43 expression were increased in the gastric smooth muscle tissues of diabetic rats. Changes in ECM of gastric smooth muscle cells were observed in DGP rats. The DGP group showed higher collagen type I content, increased expression of Caspase-1, transforming growth factor-beta 3 (TGF-β₃), and matrix metalloproteinase-2 (MMP-2), decreased tissue inhibitor of metalloproteinase-1 (TIMP-1) expression, and higher interleukin-1 beta content when compared with the control group. For gastric smooth muscle cells cultured under higher glucose, the MMP-2 and TGF-β3 expression was decreased, TGF-β1 and TIMP-1 expression was increased, the interleukin-1 beta content was decreased in cells after inhibition of NLRP3 expression; the NLRP3 and Caspase-1 expression was decreased, and adenosine triphosphate content was lower after inhibition of Cx43; the expression of NLRP3, Caspase-1, P2X7, and the membrane/cytoplasm ratio of CX43 expression was decreased in cells after inhibition of AMPK and oxidative stress, the phospho-AMPK expression was also decreased after suppressing oxidative stress. Our findings suggest that high glucose induced the activation of the AMPK-Cx43-NLRP3 pathway through oxidative stress, and this pathway was involved in the ECM remodeling of gastric smooth muscles in DGP rats by regulating the biological functions of TGF-β3, TGF-β1, MMP-2, and TIMP-1.</p></div>","PeriodicalId":9684,"journal":{"name":"Cell Stress & Chaperones","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1355814524000671/pdfft?md5=3aef01b0be0970ec7d167ee34824f45a&pid=1-s2.0-S1355814524000671-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140792351","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hsf1 and Hsf2 in normal, healthy human tissues: Immunohistochemistry provokes new questions","authors":"Matthias P. Mayer","doi":"10.1016/j.cstres.2024.04.004","DOIUrl":"10.1016/j.cstres.2024.04.004","url":null,"abstract":"<div><p>The heat shock transcription factors heat shock transcription factor 1 and Hsf2 have been studied for many years, mainly in the context of stress response and in malignant cells. Their physiological function in nonmalignant human cells under nonstress conditions is still largely unknown. To approach this important issue, Joutsen <em>et al.</em> present immunohistochemical staining data on Hsf1 and Hsf2 in 80 nonpathological human tissue samples. The wealth of these data elicits many interesting questions that will spur many future research projects.</p></div>","PeriodicalId":9684,"journal":{"name":"Cell Stress & Chaperones","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S135581452400066X/pdfft?md5=bef01fbfd2609f874f7ee7b3dc68c9f7&pid=1-s2.0-S135581452400066X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140789822","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Membraneless and membrane-bound organelles in an anhydrobiotic cell line are protected from desiccation-induced damage","authors":"Clinton J. Belott ,&nbsp;Oleg A. Gusev ,&nbsp;Takahiro Kikawada ,&nbsp;Michael A. Menze","doi":"10.1016/j.cstres.2024.04.002","DOIUrl":"https://doi.org/10.1016/j.cstres.2024.04.002","url":null,"abstract":"<div><p>Anhydrobiotic species can survive virtually complete water loss by entering a reversible ametabolic glassy state that may persist for years in ambient conditions. The Pv11 cell line was derived from the egg mass of the anhydrobiotic midge, <em>Polypedilum vanderplanki</em>, and is currently the only available anhydrobiotic cell line. Our results demonstrate that the necessary preconditioning for Pv11 cells to enter anhydrobiosis causes autophagy and reduces mitochondrial respiration by over 70%. We speculate that reorganizing cellular bioenergetics to create and conserve energy stores may be valuable to successfully recover after rehydration. Furthermore, mitochondria in preconditioned cells lose their membrane potential during desiccation but rapidly restore it within 30 min upon rehydration, demonstrating that the inner mitochondrial membrane integrity is well-preserved. Strikingly, the nucleolus remains visible immediately upon rehydration in preconditioned cells while absent in control cells. In contrast, a preconditioning-induced membraneless organelle reformed after rehydration, demonstrating that membraneless organelles in Pv11 cells can be either stabilized or recovered. Staining the endoplasmic reticulum and the Golgi apparatus revealed that these organelles fragment during preconditioning. We hypothesize that this process reduces sheering stress caused by rapid changes in cellular volume during desiccation and rehydration. Additionally, preconditioning was found to cause the filamentous-actin (F-actin) network to disassemble significantly and reduce the fusion of adjacent plasma membranes. This study offers several exciting avenues for future studies in the animal model and Pv11 cell line that will further our understanding of anhydrobiosis and may lead to advancements in storing sensitive biologics at ambient temperatures for months or years.</p></div>","PeriodicalId":9684,"journal":{"name":"Cell Stress & Chaperones","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1355814524000646/pdfft?md5=f0cb2e4d4f49fb9347b1ec3dbcd12461&pid=1-s2.0-S1355814524000646-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140633363","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Loss of the histone chaperone UNC-85/ASF1 inhibits the epigenome-mediated longevity and modulates the activity of one-carbon metabolism","authors":"Bideep Shrestha ,&nbsp;Anni I. Nieminen ,&nbsp;Olli Matilainen","doi":"10.1016/j.cstres.2024.04.003","DOIUrl":"https://doi.org/10.1016/j.cstres.2024.04.003","url":null,"abstract":"<div><p>Histone H3/H4 chaperone anti-silencing function 1 (ASF1) is a conserved factor mediating nucleosomal assembly and disassembly, playing crucial roles in processes such as replication, transcription, and DNA repair. Nevertheless, its involvement in aging has remained unclear. Here, we utilized the model organism <em>Caenorhabditis elegans</em> to demonstrate that the loss of UNC-85, the homolog of ASF1, leads to a shortened lifespan in a multicellular organism. Furthermore, we show that UNC-85 is required for epigenome-mediated longevity, as knockdown of the histone H3 lysine K4 methyltransferase <em>ash-2</em> does not extend the lifespan of <em>unc-85</em> mutants. In this context, we found that the longevity-promoting <em>ash-2</em> RNA interference enhances UNC-85 activity by increasing its nuclear localization. Finally, our data indicate that the loss of UNC-85 increases the activity of one-carbon metabolism, and that downregulation of the one-carbon metabolism component <em>dao-3</em>/<em>MTHFD2</em> partially rescues the short lifespan of <em>unc-85</em> mutants. Together, these findings reveal UNC-85/ASF1 as a modulator of the central metabolic pathway and a factor regulating a pro-longevity response, thus shedding light on a mechanism of how nucleosomal maintenance associates with aging.</p></div>","PeriodicalId":9684,"journal":{"name":"Cell Stress & Chaperones","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1355814524000658/pdfft?md5=d32243477ea21056adfa8f117b7cde58&pid=1-s2.0-S1355814524000658-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140605367","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Discovery and validation of a novel inhibitor of HYPE-mediated AMPylation","authors":"Ali Camara ,&nbsp;Heerak Chugh ,&nbsp;Alyssa George ,&nbsp;Lukas Dolidze ,&nbsp;Kevin Ryu ,&nbsp;Katrina J. Holly ,&nbsp;Daniel P. Flaherty ,&nbsp;Seema Mattoo","doi":"10.1016/j.cstres.2024.04.001","DOIUrl":"https://doi.org/10.1016/j.cstres.2024.04.001","url":null,"abstract":"<div><p>Adenosyl monophosphate (AMP)ylation (the covalent transfer of an AMP from Adenosine Triphosphate (ATP) onto a target protein) is catalyzed by the human enzyme Huntingtin Yeast Interacting Partner E (HYPE)/FicD to regulate its substrate, the heat shock chaperone binding immunoglobulin protein (BiP). HYPE-mediated AMPylation of BiP is critical for maintaining proteostasis in the endoplasmic reticulum and mounting a unfolded protein response in times of proteostatic imbalance. Thus, manipulating HYPE’s enzymatic activity is a key therapeutic strategy toward the treatment of various protein misfolding diseases, including neuropathy and early-onset diabetes associated with two recently identified clinical mutations of HYPE. Herein, we present an optimized, fluorescence polarization-based, high-throughput screening (HTS) assay to discover activators and inhibitors of HYPE-mediated AMPylation. After challenging our HTS assay with over 30,000 compounds, we discovered a novel AMPylase inhibitor, I2.10. We also determined a low micromolar IC50 for I2.10 and employed biorthogonal counter-screens to validate its efficacy against HYPE’s AMPylation of BiP. Further, we report low cytotoxicity of I2.10 on human cell lines. We thus established an optimized, high-quality HTS assay amenable to tracking HYPE’s enzymatic activity at scale, and provided the first novel small-molecule inhibitor capable of perturbing HYPE-directed AMPylation of BiP <em>in vitro</em>. Our HTS assay and I2.10 compound serve as a platform for further development of HYPE-specific small-molecule therapeutics.</p></div>","PeriodicalId":9684,"journal":{"name":"Cell Stress & Chaperones","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1355814524000634/pdfft?md5=5911a65888b992c1e98a5c34c57cba1f&pid=1-s2.0-S1355814524000634-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140631465","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"miR-92a-3p regulates ethanol-induced apoptosis in H9c2 cardiomyocytes","authors":"Yan Meng ,&nbsp;Zhenzhen Hu ,&nbsp;Chenyi Zhang ,&nbsp;Hao Bai ,&nbsp;Zhaoping Li ,&nbsp;Xinru Guo ,&nbsp;Liyong Chen","doi":"10.1016/j.cstres.2024.03.009","DOIUrl":"https://doi.org/10.1016/j.cstres.2024.03.009","url":null,"abstract":"<div><p>The role of miR-92a-3p in the ethanol-induced apoptosis of H9c2 cardiomyocytes remains unclear. In this study, we explored the role of miR-92a-3p in the ethanol-induced apoptosis of H9c2 cardiomyocytes and identified its target genes and signaling pathways. H9c2 cells were cultured with or without 100 mM ethanol for 24 h. The differential expression of miR-92a-3p was verified in H9c2 cells through reverse transcription-quantitative polymerase chain reaction (RT-qPCR). To manipulate the expression of miR-92a-3p, both a mimic and an inhibitor were transfected into H9c2 cells. An Annexin V–fluorescein isothiocyanate/propidium iodide apoptosis detection kit and apoptosis-related antibodies were used for apoptosis detection through flow cytometry and Western blotting, respectively. Target genes were verified through RT-qPCR, Western blotting, and double luciferase reporter gene assays. miR-92a-3p was significantly overexpressed in ethanol-stimulated H9c2 cardiomyocytes (<em>P</em> &lt; 0.001). After ethanol stimulation, H9c2 myocardial cells exhibited increased apoptosis. The apoptosis rate was higher in the miR-92a-3p mimic group than in the control group. However, the apoptosis rate was lower in the miR-92a-3p inhibitor group than in the control group, indicating that miR-92a-3p promotes the ethanol-induced apoptosis of H9c2 myocardial cells. RT-qPCR and Western blotting revealed that the miR-92a-3p mimic and inhibitor significantly regulated the mRNA and protein expression levels of mitogen- and stress-activated protein kinase 2 and cyclic AMP-responsive element-binding protein 3-like protein 2 (CREB3L2), suggesting that miR-92a-3p promotes the apoptosis of H9c2 cardiomyocytes by inhibiting the MSK2/CREB/Bcl-2 pathway. Therefore, the apoptosis of H9c2 cardiomyocytes increases after ethanol stimulation, and miR-92a-3p can directly target MSK2 and CREB3L2, thereby promoting the ethanol-induced apoptosis of H9c2 myocardial cells.</p></div>","PeriodicalId":9684,"journal":{"name":"Cell Stress & Chaperones","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1355814524000610/pdfft?md5=4b6d513bfaa64c78cfbb479e78b60d49&pid=1-s2.0-S1355814524000610-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140553990","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Plasmodium falciparum heat shock proteins as antimalarial drug targets: An update","authors":"Tanveer Ahmad ,&nbsp;Bushra A. Alhammadi ,&nbsp;Shaikha Y. Almaazmi ,&nbsp;Sahar Arafa ,&nbsp;Gregory L. Blatch ,&nbsp;Tanima Dutta ,&nbsp;Jason E. Gestwicki ,&nbsp;Robert A. Keyzers ,&nbsp;Addmore Shonhai ,&nbsp;Harpreet Singh","doi":"10.1016/j.cstres.2024.03.007","DOIUrl":"10.1016/j.cstres.2024.03.007","url":null,"abstract":"<div><p>Global efforts to eradicate malaria are threatened by multiple factors, particularly the emergence of antimalarial drug resistant strains of <em>Plasmodium falciparum</em>. Heat shock proteins (HSPs), particularly <em>P. falciparum</em> HSPs (PfHSPs), represent promising drug targets due to their essential roles in parasite survival and virulence across the various life cycle stages. Despite structural similarities between human and malarial HSPs posing challenges, there is substantial evidence for subtle differences that could be exploited for selective drug targeting. This review provides an update on the potential of targeting various PfHSP families (particularly PfHSP40, PfHSP70, and PfHSP90) and their interactions within PfHSP complexes as a strategy to develop new antimalarial drugs. In addition, the need for a deeper understanding of the role of HSP complexes at the host–parasite interface is highlighted, especially heterologous partnerships between human and malarial HSPs, as this opens novel opportunities for targeting protein–protein interactions crucial for malaria parasite survival and pathogenesis.</p></div>","PeriodicalId":9684,"journal":{"name":"Cell Stress & Chaperones","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1355814524000592/pdfft?md5=da108f138aaca73d689e40be490fca6e&pid=1-s2.0-S1355814524000592-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140189452","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Extracellular metallothionein as a therapeutic target in the early progression of type 1 diabetes","authors":"Clare K. Melchiorre ,&nbsp;Matthew D. Lynes ,&nbsp;Sadikshya Bhandari ,&nbsp;Sheng-Chiang Su ,&nbsp;Christian M. Potts ,&nbsp;Amy V. Thees ,&nbsp;Carol E. Norris ,&nbsp;Lucy Liaw ,&nbsp;Yu-Hua Tseng ,&nbsp;Michael A. Lynes","doi":"10.1016/j.cstres.2024.03.005","DOIUrl":"10.1016/j.cstres.2024.03.005","url":null,"abstract":"<div><p>Type 1 diabetes (T1D) is characterized by lymphocyte infiltration into the pancreatic islets of Langerhans, leading to the destruction of insulin-producing beta cells and uncontrolled hyperglycemia. In the nonobese diabetic (NOD) murine model of T1D, the onset of this infiltration starts several weeks before glucose dysregulation and overt diabetes. Recruitment of immune cells to the islets is mediated by several chemotactic cytokines, including CXCL10, while other cytokines, including SDF-1α, can confer protective effects. Global gene expression studies of the pancreas from prediabetic NOD mice and single-cell sequence analysis of human islets from prediabetic, autoantibody-positive patients showed an increased expression of metallothionein (MT), a small molecular weight, cysteine-rich metal-binding stress response protein. We have shown that beta cells can release MT into the extracellular environment, which can subsequently enhance the chemotactic response of Th1 cells to CXCL10 and interfere with the chemotactic response of Th2 cells to SDF-1α. These effects can be blocked <em>in vitro</em> with a monoclonal anti-MT antibody, clone UC1MT. When administered to NOD mice before the onset of diabetes, UC1MT significantly reduces the development of T1D. Manipulation of extracellular MT may be an important approach to preserving beta cell function and preventing the development of T1D.</p></div>","PeriodicalId":9684,"journal":{"name":"Cell Stress & Chaperones","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1355814524000579/pdfft?md5=8f8a25f3c455a22914b8fd930aacb052&pid=1-s2.0-S1355814524000579-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140136565","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Autorepression of yeast Hsp70 cochaperones by intramolecular interactions involving their J-domains","authors":"Mathieu E. Rebeaud ,&nbsp;Satyam Tiwari ,&nbsp;Bruno Fauvet ,&nbsp;Adelaïde Mohr ,&nbsp;Pierre Goloubinoff ,&nbsp;Paolo De Los Rios","doi":"10.1016/j.cstres.2024.03.008","DOIUrl":"10.1016/j.cstres.2024.03.008","url":null,"abstract":"<div><p>The 70 kDa heat shock protein (Hsp70) chaperones control protein homeostasis in all ATP-containing cellular compartments. J-domain proteins (JDPs) coevolved with Hsp70s to trigger ATP hydrolysis and catalytically upload various substrate polypeptides in need to be structurally modified by the chaperone. Here, we measured the protein disaggregation and refolding activities of the main yeast cytosolic Hsp70, Ssa1, in the presence of its most abundant JDPs, Sis1 and Ydj1, and two swap mutants, in which the J-domains have been interchanged. The observed differences by which the four constructs differently cooperate with Ssa1 and cooperate with each other, as well as their observed intrinsic ability to bind misfolded substrates and trigger Ssa1′s ATPase, indicate the presence of yet uncharacterized intramolecular dynamic interactions between the J-domains and the remaining C-terminal segments of these proteins. Taken together, the data suggest an autoregulatory role to these intramolecular interactions within both type A and B JDPs, which might have evolved to reduce energy-costly ATPase cycles by the Ssa1–4 chaperones that are the most abundant Hsp70s in the yeast cytosol.</p></div>","PeriodicalId":9684,"journal":{"name":"Cell Stress & Chaperones","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1355814524000609/pdfft?md5=3840b17933f941a28bef6070677044c7&pid=1-s2.0-S1355814524000609-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140193476","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Impact of histone deacetylase inhibition and arimoclomol on heat shock protein expression and disease biomarkers in primary culture models of familial ALS","authors":"Mario Fernández Comaduran ,&nbsp;Sandra Minotti ,&nbsp;Suleima Jacob-Tomas ,&nbsp;Javeria Rizwan ,&nbsp;Nancy Larochelle ,&nbsp;Richard Robitaille ,&nbsp;Chantelle F. Sephton ,&nbsp;Maria Vera ,&nbsp;Josephine N. Nalbantoglu ,&nbsp;Heather D. Durham","doi":"10.1016/j.cstres.2024.03.010","DOIUrl":"https://doi.org/10.1016/j.cstres.2024.03.010","url":null,"abstract":"<div><p>Protein misfolding and mislocalization are common themes in neurodegenerative disorders, including motor neuron disease, and amyotrophic lateral sclerosis (ALS). Maintaining proteostasis is a crosscutting therapeutic target, including the upregulation of heat shock proteins (HSP) to increase chaperoning capacity. Motor neurons have a high threshold for upregulating stress-inducible HSPA1A, but constitutively express high levels of HSPA8. This study compared the expression of these HSPs in cultured motor neurons expressing three variants linked to familial ALS: TAR DNA binding protein 43 kDa (TDP-43)^G348C, fused in sarcoma (FUS)^R521G, or superoxide dismutase I (SOD1)^G93A. All variants were poor inducers of <em>Hspa1a,</em> and reduced levels of <em>Hspa8</em> mRNA and protein, indicating multiple compromises in chaperoning capacity. To promote HSP expression, cultures were treated with the putative HSP coinducer, arimoclomol, and class I histone deacetylase inhibitors, to promote active chromatin for transcription, and with the combination. Treatments had variable, often different effects on the expression of <em>Hspa1a</em> and <em>Hspa8</em>, depending on the ALS variant expressed, mRNA distribution (somata and dendrites), and biomarker of toxicity measured (histone acetylation, maintaining nuclear TDP-43 and the neuronal Brm/Brg-associated factor chromatin remodeling complex component Brg1, mitochondrial transport, FUS aggregation). Overall, histone deacetylase inhibition alone was effective on more measures than arimoclomol. As in the FUS model, arimoclomol failed to induce HSPA1A or preserve <em>Hspa8</em> mRNA in the TDP-43 model, despite preserving nuclear TDP-43 and Brg1, indicating neuroprotective properties other than HSP induction. The data speak to the complexity of drug mechanisms against multiple biomarkers of ALS pathogenesis, as well as to the importance of HSPA8 for neuronal proteostasis in both somata and dendrites.</p></div>","PeriodicalId":9684,"journal":{"name":"Cell Stress & Chaperones","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1355814524000622/pdfft?md5=e00b6b10c56dbd12b029843d1b93d135&pid=1-s2.0-S1355814524000622-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140539607","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}