European journal of cell biology最新文献

{"title":"Role of the sodium/calcium exchanger type 3 in cancer cells","authors":"Galvankova Kristina ,&nbsp;Rezuchova Ingeborg ,&nbsp;Klena Ladislav ,&nbsp;Grman Marian ,&nbsp;Gazova Simona ,&nbsp;Liskova Veronika ,&nbsp;Kozovska Zuzana ,&nbsp;Roller Ladislav ,&nbsp;Babula Petr ,&nbsp;Krizanova Olga","doi":"10.1016/j.ejcb.2025.151493","DOIUrl":"10.1016/j.ejcb.2025.151493","url":null,"abstract":"<div><div>The sodium/calcium exchanger (NCX) type 1 has been well described in various cancers, but little is known about the other two NCX types (NCX2 and NCX3). In this study, we used the selective blocker of NCX3 – YM-244769 to investigate changes in apoptosis induction, migration, proliferation, intracellular calcium and ATP in four cancer cell lines – DLD1, HeLa, MDA-MB-231 and JIMT1. In all four cell lines we observed a concentration-dependent increase in the number of apoptotic cells, as well as reduced migration and proliferation. Induction of hypoxic conditions did not alter the response of these cells to YM-244769 in any of the above-mentioned parameters. These results indicate the role of NCX3 in cancer cell migration, proliferation and apoptosis, as inhibition of NCX1 by the specific blocker SEA0400 had no significant effect on these parameters. However, we verified the effect of NCX3 inhibition by using CRISPR/Cas9 to generate clones in which the <em>SLC8A3</em> (NCX3) gene was deleted, and we obtained the same results. In addition, mitochondrial respiration was impaired in the clones with NCX3 knocked-out, suggesting that NCX3 also play a role in bioenergetics. In conclusion, we have clearly shown that NCX3 plays an important anti-apoptotic, pro-migratory and proliferative role in the cancer cells by affecting mitochondrial bioenergetics, thus supporting their survival and fate.</div></div>","PeriodicalId":12010,"journal":{"name":"European journal of cell biology","volume":"104 2","pages":"Article 151493"},"PeriodicalIF":4.5,"publicationDate":"2025-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143904048","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Combining prelamin A accumulation and oxidative stress: A strategy to target glioblastoma","authors":"Maria Vittoria Marvi ,&nbsp;Camilla Evangelisti ,&nbsp;Camilla Bruna Cerchier ,&nbsp;Antonietta Fazio ,&nbsp;Irene Neri ,&nbsp;Foteini-Dionysia Koufi ,&nbsp;William Blalock ,&nbsp;Vittoria Cenni ,&nbsp;Matteo Zoli ,&nbsp;Sofia Asioli ,&nbsp;Luca Morandi ,&nbsp;Enrico Franceschi ,&nbsp;Lucia Manzoli ,&nbsp;Cristina Capanni ,&nbsp;Stefano Ratti","doi":"10.1016/j.ejcb.2025.151491","DOIUrl":"10.1016/j.ejcb.2025.151491","url":null,"abstract":"<div><div>Glioblastoma is the most aggressive and prevalent tumor of the Central Nervous System (CNS) with limited treatment options and poor patient outcomes. Standard therapies, including surgery, radiation, and chemotherapy, provide only modest survival benefits, highlighting the need for innovative therapeutic approaches. This study investigates a novel strategy targeting prelamin A processing in glioblastoma cells. By inhibiting the farnesyltransferase enzyme using SCH66336 (Lonafarnib), we promote the accumulation of lamin A precursor (prelamin A) in glioblastoma cells, thereby increasing their susceptibility to oxidative stress induced by Menadione administration, while sparing normal human astrocytes. Notably, the combined SCH66336-Menadione treatment reduced cell proliferation, modified the expression of stemness markers, and decreased viability in patient-derived glioblastoma stem cells, which represent the population responsible for tumor aggressiveness and recurrence. These findings indicate that inhibiting prelamin A processing could be a potential strategy to reduce glioblastoma aggressiveness and enhance therapeutic outcomes, particularly for treatment-resistant glioblastoma stem cell populations. This approach shows potential for integrating prelamin A processing disruption as a complementary strategy in glioblastoma therapy.</div></div>","PeriodicalId":12010,"journal":{"name":"European journal of cell biology","volume":"104 2","pages":"Article 151491"},"PeriodicalIF":4.5,"publicationDate":"2025-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143885938","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Holotomographic microscopy reveals label-free quantitative dynamics of endothelial cells during endothelialization","authors":"William D. Leineweber ,&nbsp;Gabriela Acevedo Munares ,&nbsp;Christian Leycam ,&nbsp;Raul Michael ,&nbsp;Juliette Noyer ,&nbsp;Patrick Jurney","doi":"10.1016/j.ejcb.2025.151492","DOIUrl":"10.1016/j.ejcb.2025.151492","url":null,"abstract":"<div><div>Holotomograhic microscopy (HTM) has emerged as a non-invasive imaging technique that offers high-resolution, quantitative 3D imaging of biological samples. This study explores the application of HTM in examining endothelial cells (ECs). HTM overcomes the limitations of traditional microscopy methods in capturing the real-time dynamics of ECs by leveraging the refractive index (RI) to map 3D distributions label-free. This work demonstrates the utility of HTM in visualizing key cellular processes during endothelialization, wherein ECs anchor, adhere, migrate, and proliferate. Leveraging the high resolution and quantitative power of HTM, we show that lipid droplets and mitochondria are readily visualized, enabling more comprehensive studies on their respective roles during endothelialization. The study highlights how HTM on a commercial instrument can uncover novel insights into HUVEC cell behavior, offering potential applications in medical diagnostics and research, particularly in developing treatments for cardiovascular diseases. This advanced imaging technique not only enhances our understanding of EC biology but also presents a significant step forward in the study of cardiovascular diseases, providing a robust platform for future research and therapeutic development.</div></div>","PeriodicalId":12010,"journal":{"name":"European journal of cell biology","volume":"104 2","pages":"Article 151492"},"PeriodicalIF":4.5,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143878935","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Viral vaccines promote endoplasmic reticulum stress-induced unfolding protein response in teleost erythrocytes","authors":"Maria Salvador-Mira ,&nbsp;Paula Gimenez-Moya ,&nbsp;Alba Manso-Aznar ,&nbsp;Ester Sánchez-Córdoba ,&nbsp;Manuel A. Sevilla-Diez ,&nbsp;Veronica Chico ,&nbsp;Ivan Nombela ,&nbsp;Sara Puente-Marin ,&nbsp;Nerea Roher ,&nbsp;Luis Perez ,&nbsp;Tanja Dučić ,&nbsp;Núria Benseny-Cases ,&nbsp;Ana Joaquina Perez-Berna ,&nbsp;Maria del Mar Ortega-Villaizan","doi":"10.1016/j.ejcb.2025.151490","DOIUrl":"10.1016/j.ejcb.2025.151490","url":null,"abstract":"<div><div>Most available evidence points to a proviral role for endoplasmic reticulum (ER) stress, as many viruses exploit it to promote viral replication. In contrast, few studies have linked ER stress to the antiviral immune response, and even fewer to the vaccine-induced immune response. In this work, we demonstrated that ER stress is a key molecular link in the immune response of teleost erythrocytes or red blood cells (RBCs) under vaccine stimulation. Moreover, the unfolded protein response (UPR^ER) triggered by ER stress may work together with autophagy and related cellular mechanisms as part of a coordinated immune response in RBCs. We unveiled biochemical changes in the lipid-protein profile of vaccine-treated RBCs by synchrotron radiation-based Fourier transform infrared microspectroscopy (SR-µFTIR) associated with the modulation of ER expansion, increased mitochondrial number, and vesicular structures detected by soft X-ray cryotomography (cryo-SXT). We found a positive correlation between both morphological and biochemical changes and the expression of genes related to UPR^ER, autophagy, mitochondrial stress, vesicle trafficking, and extracellular vesicle release. These processes in RBCs are ideal cellular targets for the development of more specific prophylactic tools with greater immunogenic capacity than currently available options.</div></div>","PeriodicalId":12010,"journal":{"name":"European journal of cell biology","volume":"104 2","pages":"Article 151490"},"PeriodicalIF":4.5,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143844081","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Galectin-8 drives ERK-dependent mitochondrial fragmentation, perinuclear relocation and mitophagy, with metabolic adaptations for cell proliferation","authors":"Adely de la Peña ,&nbsp;Claudio Retamal ,&nbsp;Francisca Pérez-Molina ,&nbsp;Nicole Díaz-Valdivia ,&nbsp;Francisco Veloso-Bahamondes ,&nbsp;Diego Tapia ,&nbsp;Jorge Cancino ,&nbsp;Felix Randow ,&nbsp;Alfonso González ,&nbsp;Claudia Oyanadel ,&nbsp;Andrea Soza","doi":"10.1016/j.ejcb.2025.151488","DOIUrl":"10.1016/j.ejcb.2025.151488","url":null,"abstract":"<div><div>Mitochondria adapt to the cell proliferative demands induced by growth factors through dynamic changes in morphology, distribution, and metabolic activity. Galectin-8 (Gal-8), a carbohydrate-binding protein that promotes cell proliferation by transactivating the EGFR-ERK signaling pathway, is overexpressed in several cancers. However, its impact on mitochondrial dynamics during cell proliferation remains unknown. Using MDCK and RPTEC kidney epithelial cells, we demonstrate that Gal-8 induces mitochondrial fragmentation and perinuclear redistribution. Additionally, mitochondria adopt donut-shaped morphologies, and live-cell imaging with two Keima-based reporters demonstrates Gal-8-induced mitophagy. ERK signaling inhibition abrogates all these Gal-8-induced mitochondrial changes and cell proliferation. Studies with established mutant versions of Gal-8 and CHO cells reveal that mitochondrial changes and proliferative response require interactions between the N-terminal carbohydrate recognition domain of Gal-8 and α-2,3-sialylated N-glycans at the cell surface. DRP1, a key regulator of mitochondrial fission, becomes phosphorylated in MDCK cells or overexpressed in RPTEC cells in an ERK-dependent manner, mediating mitochondrial fragmentation and perinuclear redistribution. Bafilomycin A abrogates Gal-8-induced cell proliferation, suggesting that mitophagy serves as an adaptation to cell proliferation demands. Functional analysis under Gal-8 stimulation shows that mitochondria maintain an active electron transport chain, partially uncoupled from ATP synthesis, and an increased membrane potential, indicative of healthy mitochondria. Meanwhile, the cells exhibit increased extracellular acidification rate and lactate production via aerobic glycolysis, a hallmark of an active proliferative state. Our findings integrate mitochondrial dynamics with metabolic adaptations during Gal-8-induced cell proliferation, with potential implications for physiology, disease, and therapeutic strategies.</div></div>","PeriodicalId":12010,"journal":{"name":"European journal of cell biology","volume":"104 2","pages":"Article 151488"},"PeriodicalIF":4.5,"publicationDate":"2025-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143800685","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":"Versatility of vimentin assemblies: From filaments to biomolecular condensates and back","authors":"Dolores Pérez-Sala,&nbsp;Silvia Zorrilla","doi":"10.1016/j.ejcb.2025.151487","DOIUrl":"10.1016/j.ejcb.2025.151487","url":null,"abstract":"<div><div>Cytoskeletal structures shape and confer resistance to cells. The intermediate filament protein vimentin forms versatile structures that play key roles in cytoskeletal crosstalk, in the integration of cellular responses to a variety of external and internal cues, and in the defense against stress. Such multifaceted roles can be fulfilled thanks to the vast variety of vimentin proteoforms, which in turn arise from the combinations of a myriad of tightly regulated posttranslational modifications. Diverse vimentin proteoforms will differentially shape its polymeric assemblies, underlying vimentin ability to organize in filaments, bundles, squiggles, droplets, cell surface-bound and/or various secreted forms. Interestingly, certain vimentin dots or droplets have been lately categorized as biomolecular condensates. Biomolecular condensates are phase-separated membraneless structures that are critical for the organization of cellular components and play important roles in pathophysiology. Recent findings have unveiled the importance of low complexity sequence domains in vimentin filament assembly. Moreover, several oxidants trigger the transition of vimentin filaments into phase-separated biomolecular condensates, a reversible process that may provide clues on the role of condensates as seeds for filament formation. Revisiting previous results in the light of recent knowledge prompts the hypothesis that vimentin condensates could play a role in traffic of filament precursors, cytoskeletal crosstalk and cellular responses to stress. Deciphering the “vimentin posttranslational modification code”, that is, the structure-function relationships of vimentin proteoforms, constitutes a major challenge to understand the regulation of vimentin behavior and its multiple personalities. This will contribute to unveil essential cellular mechanisms and foster novel opportunities for drug discovery.</div></div>","PeriodicalId":12010,"journal":{"name":"European journal of cell biology","volume":"104 2","pages":"Article 151487"},"PeriodicalIF":4.5,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143785628","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":"Human pluripotent stem cell-derived intestinal organoids for pharmacokinetic studies","authors":"Takumi Saito ,&nbsp;Junichiro Amako ,&nbsp;Teruhiko Watanabe ,&nbsp;Nobuaki Shiraki ,&nbsp;Shoen Kume","doi":"10.1016/j.ejcb.2025.151489","DOIUrl":"10.1016/j.ejcb.2025.151489","url":null,"abstract":"<div><div>The human small intestine is essential for orally administered drugs' absorption, metabolism, and excretion. Human induced pluripotent stem cell (hiPSC)-derived intestinal epithelial cells (IECs) offer a useful model for evaluating drug candidate compounds. We previously reported a protocol to generate matured enterocyte-like cells that exhibit P-gp-mediated efflux and cytochrome P450 3A (CYP3A)-mediated metabolism from human iPSCs. However, under the current protocols, generating iPSC-derived intestinal enterocyte-like cells requires a multi-step differentiation procedure and is time-consuming. Recent progress in intestinal organoid (IO) study provides an understanding of the growth factors that enable the maintenance of adult stem cells. Here, we established an easily accessible protocol using a direct 3D cluster culture to derive IOs from hiPSCs (iPSC-IOs) with high self-proliferative ability. The hiPSC-IOs can be propagated for a long-term and maintained capacity to differentiate and can be cryopreserved. Upon seeding on a two-dimensional monolayer, hiPSC-IOs gave rise to the intestinal epithelial cells (IECs) containing mature cell types of the intestine. The hiPSC-IOs-derived IECs contain enterocytes that show CYP metabolizing enzyme and transporter activities and can be used for pharmacokinetic studies.</div></div>","PeriodicalId":12010,"journal":{"name":"European journal of cell biology","volume":"104 2","pages":"Article 151489"},"PeriodicalIF":4.5,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143791048","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":"Activity and function of auxiliary fluxes of glucose metabolism in response to physiological normoxia (5 % O2) during long-term Adipose-Derived Stem/Stromal cell culture","authors":"Paulina Rybkowska ,&nbsp;Maria Kawalec ,&nbsp;Dorota Dymkowska ,&nbsp;Klaudia Radoszkiewicz ,&nbsp;Barbara Zabłocka ,&nbsp;Krzysztof Zabłocki ,&nbsp;Anna Sarnowska","doi":"10.1016/j.ejcb.2025.151486","DOIUrl":"10.1016/j.ejcb.2025.151486","url":null,"abstract":"<div><div>Energy metabolism homeostasis emerges as a dominant element influencing mesenchymal stem/stromal cells’ trajectory of development. The predominant glycolysis activity is a primary driver of cell proliferation and maintenance of the high-energetic state. Here, we examined the functions of two crucial auxiliary pathways: the phosphate-pentose pathway (PPP) and fructose-2,6-biphosphate pathway (FBP) to evaluate their impact on the therapeutic potential of Adipose-Derived Stem/Stromal cells (ASCs) during prolonged culture in various oxygen conditions: 5 % O₂ - physiological normoxia or 21 % O₂ - atmospheric oxygen. Our findings demonstrate that ASCs cultured in 5 % O₂ increased the rate of proliferation, migration, and expression of stemness factors, which is prominent during the initial and middle passages. Additionally, ASCs cultured in a 5 % O₂ exhibited heightened protection mechanisms against free radicals, increased LDH gene expression, and elevated extracellular acidification rate (ECAR). By estimating the HIF-1α level, we concluded that 5 % oxygen conditions were insufficient to induce a profound hypoxic state in ASCs. However, at the protein level, both the PPP and FBP pathways appeared to be more active in young (2-passage) cells, regardless of oxygen conditions, and their activity diminished over time. Additionally, the chemical suppression of G6PDH by Polydatin and inhibition of PFKFB3 by PFK-158 in ASCs (passage-2) revealed dose- and time-dependent effect on decreasing migratory capabilities of cells. Nevertheless, our work underscores the adaptable nature of ASC metabolism to prevailing external conditions, with the aging of the culture contributing to the decline in glycolysis-associated auxiliary pathways.</div></div>","PeriodicalId":12010,"journal":{"name":"European journal of cell biology","volume":"104 2","pages":"Article 151486"},"PeriodicalIF":4.5,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143767181","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":"Advances in modeling the Charcot-Marie-Tooth disease: Human induced pluripotent stem cell-derived Schwann cells harboring SH3TC2 variants","authors":"Camille Loret ,&nbsp;Camille Scherrer ,&nbsp;Amandine Rovini ,&nbsp;Ioanna Pyromali ,&nbsp;Pierre-Antoine Faye ,&nbsp;Angélique Nizou ,&nbsp;Franck Sturtz ,&nbsp;Frédéric Favreau ,&nbsp;Anne-Sophie Lia","doi":"10.1016/j.ejcb.2025.151485","DOIUrl":"10.1016/j.ejcb.2025.151485","url":null,"abstract":"<div><div>Human induced pluripotent stem cells (hiPSCs) represent a powerful tool for investigating neuropathological disorders, such as Charcot-Marie-Tooth disease (CMT), the most prevalent inherited peripheral neuropathy, where the cells of interest are hardly accessible. Advancing the development of appropriate cellular models is crucial for studying the disease’s pathophysiology. In this study, we present the first two isogenic hiPSC-derived Schwann cell models for studying CMT4C, also known as AR-CMTde-<em>SH3TC2</em>. This subtype of CMT is associated with alterations in <em>SH3TC2</em> and is the most prevalent form of autosomal recessive demyelinating CMT. We aimed to study the impact of two nonsense mutations in <em>SH3TC2</em>. To achieve this, we used two CRISPR hiPSC clones, one carrying a homozygous nonsense mutation: c.211C&gt;T, p.Gln71*, and the other one, carrying the most common AR-CMTde-<em>SH3TC2</em> alteration, c.2860G&gt;A, p.Arg954*. To study the endogenous expression of SH3TC2 in the cells mainly altered in AR-CMTde-<em>SH3TC2</em>, we initiated the differentiation of both our CMT clones and their isogenic control into Schwann cells (SCs). This study represents the first <em>in vitro</em> investigation of human endogenous SH3TC2 expression in AR-CMTde-<em>SH3TC2</em> hiPSC-derived SC models, allowing for the examination of its expression and of its cellular impact. By comparing this AR-CMTde-<em>SH3TC2</em> models to the control one, we observed disparities in RNA and protein expression of SH3TC2. Additionally, our RNA and coculture experiments with hiPSC-derived motor neurons (MNs) revealed delayed maturation of SCs and a reduced ability of SH3TC2-deficient SCs to sustain motor neuron culture. Our findings also demonstrated a disability in receptor recycling in SH3TC2-deficient cells, depending on the AR-CMTde-<em>SH3TC2</em> alteration. These hiPSC-derived-SC models further provide a new modelling tool for studying Schwann cell contribution to CMT4C.</div></div>","PeriodicalId":12010,"journal":{"name":"European journal of cell biology","volume":"104 2","pages":"Article 151485"},"PeriodicalIF":4.5,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143705375","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":"iPSC screening identifies CACNA2D2 as a potential therapeutic target for FTLD-Tau","authors":"Keiko Imamura ,&nbsp;Ayako Nagahashi ,&nbsp;Aya Okusa ,&nbsp;Tomoki Sakasai ,&nbsp;Kayoko Tsukita ,&nbsp;Yumiko Kutoku ,&nbsp;Yutaka Ohsawa ,&nbsp;Yoshihide Sunada ,&nbsp;Naruhiko Sahara ,&nbsp;Nicholas M. Kanaan ,&nbsp;Makoto Higuchi ,&nbsp;Kohji Mori ,&nbsp;Manabu Ikeda ,&nbsp;Haruhisa Inoue","doi":"10.1016/j.ejcb.2025.151484","DOIUrl":"10.1016/j.ejcb.2025.151484","url":null,"abstract":"<div><div>Frontotemporal Lobar Degeneration (FTLD) is a neurodegenerative disorder that affects the frontal and temporal lobes, which are crucial for regulating personality, behavior, and language. Pathologically, FTLD is characterized by Tau protein accumulation and neuronal death. In our effort to identify disease-modifying treatments, we conducted drug screening using neurons derived from induced pluripotent stem cells (iPSCs) of FTLD-Tau patients. This screening identified gabapentin as an existing drug that suppresses neuronal cell death with suppressed accumulation of Tau oligomers. Treatment with gabapentinoids, including pregabalin and mirogabalin, demonstrated similar neuroprotective effects. These compounds bind to the α2δ subunit of voltage-dependent calcium channels and specifically target the two isoforms α2δ-1 and α2δ-2. To determine which isoform is involved in the neurodegeneration seen in FTLD-Tau, we employed a knockout approach using iPSCs, which revealed that α2δ-2, encoded by CACNA2D2, plays a key role in the degeneration of FTLD-Tau neurons. Moreover, Neural organoids of FTLD-Tau exhibited features indicative of neurodegeneration, and CACNA2D2 knockout reversed a part of the gene expression alterations associated with these neurodegenerative features. These findings suggest that α2δ-2 may be a promising target for disease-modifying therapies in FTLD-Tau.</div></div>","PeriodicalId":12010,"journal":{"name":"European journal of cell biology","volume":"104 2","pages":"Article 151484"},"PeriodicalIF":4.5,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143724353","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}