Cellular and Molecular Life Sciences最新文献

{"title":"Dissecting inflammation in the immunemetabolomic era.","authors":"Patricia P Ogger, Peter J Murray","doi":"10.1007/s00018-025-05715-8","DOIUrl":"https://doi.org/10.1007/s00018-025-05715-8","url":null,"abstract":"<p><p>The role of immune metabolism, specific metabolites and cell-intrinsic and -extrinsic metabolic states across the time course of an inflammatory response are emerging knowledge. Targeted and untargeted metabolomic analysis is essential to understand how immune cells adapt their metabolic program throughout an immune response. In addition, metabolomic analysis can aid to identify pathophysiological patterns in inflammatory disease. Here, we discuss new metabolomic findings within the transition from inflammation to resolution, focusing on three key programs of immunity: Efferocytosis, IL-10 signaling and trained immunity. Particularly the tryptophan-derived metabolite kynurenine was identified as essential for efferocytosis and inflammation resolution as well as a potential biomarker in diverse inflammatory conditions. In summary, metabolomic analysis and integration with transcriptomic and proteomic data, high resolution imaging and spatial information is key to unravel metabolic drivers and dependencies during inflammation and progression to tissue-repair.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"182"},"PeriodicalIF":6.2,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12037969/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143961473","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Single-cell multi-dimensional data analysis decodes RNF19A-mediated drug resistance in rheumatoid arthritis fibroblast-like synoviocytes: mechanisms and biological insights.","authors":"Xin Luo, Ning Tang, Yijun Ren, Jingchen Li, Huancheng Zhu, Song Wu, Zhiyu Ding","doi":"10.1007/s00018-025-05707-8","DOIUrl":"https://doi.org/10.1007/s00018-025-05707-8","url":null,"abstract":"<p><p>Rheumatoid arthritis (RA) is a prevalent autoimmune disease, affecting approximately 1% of the global population. Methotrexate (MTX) is the most widely prescribed drug for RA treatment; however, its efficacy is often limited, with resistance frequently observed. Fibroblast-like synoviocytes (FLS) play a pivotal role in RA progression and are closely linked to drug resistance, although the underlying mechanisms remain poorly understood. In this study, we conducted a comprehensive analysis of public single-cell transcriptomics data from osteoarthritis and rheumatoid arthritis synovial tissues, identifying RNF19A as a gene potentially associated with RA resistance in FLS. Our findings indicate that RNF19A is significantly overexpressed in drug-resistant FLS and is closely associated with the dysregulation of FLS proliferation, migration, invasion, and apoptosis. Furthermore, we demonstrated that RNF19A promotes functional disruption in FLS by ubiquitinating and degrading MKP-1, thereby activating the MAPK signaling pathway. This activation also facilitates the nuclear translocation of ZBTB20, an upstream transcription factor of RNF19A, which further enhances RNF19A transcription. This biological process creates a positive feedback loop in FLS, contributing to RA resistance-a mechanism that was also validated in vivo. In summary, this study is the first to underscore the crucial role of RNF19A in mediating drug resistance in RA FLS, elucidating the underlying biological processes, and providing novel insights into RA pathogenesis, thereby offering a new experimental foundation for RA drug development.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"180"},"PeriodicalIF":6.2,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12037462/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143954944","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Structural flexibility in the ordered domain of the dengue virus strain 2 capsid protein is critical for chaperoning viral RNA replication.","authors":"Kamal K Sharma, Palur Venkata Raghuvamsi, Daniel Y K Aik, Jan K Marzinek, Peter J Bond, Thorsten Wohland","doi":"10.1007/s00018-025-05712-x","DOIUrl":"https://doi.org/10.1007/s00018-025-05712-x","url":null,"abstract":"<p><p>Viral replication necessitates intricate nucleic acid rearrangements, including annealing and strand displacement to achieve the viral RNA functional structure. Often a single RNA chaperone performs these seemingly incompatible functions. This raises the question of what structural and dynamic features of such chaperones govern distinct RNA rearrangements. While cationic intrinsically disordered regions promote annealing by playing a charge-screening role, how the same chaperone mediates strand displacement remains elusive. Here, we investigate the annealing and strand displacement of the 5' upstream AUG region (5UAR) as chaperoned by the Dengue virus strain 2 capsid protein (Denv2C) as a model RNA chaperone. Through single molecule analysis and molecular simulations, we demonstrate that Denv2C regulates nucleic acid melting, folding, annealing, and strand displacement via flexibility in its ordered region. A mutation that renders the Denv2C ordered region rigid, converts Denv2C into a mere annealer. Our findings underscore the role of Denv2C's disordered region as a \"macromolecular counterion\" during RNA annealing, while a flexible ordered region is crucial for effective strand displacement.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"184"},"PeriodicalIF":6.2,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12037954/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143954857","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Progranulin enhances M2 macrophage polarization and renal fibrosis by modulating autophagy in chronic kidney disease.","authors":"Wei-Chao Tu, Yi-Kun He, Da-Wei Wang, Shao-Xiong Ming, Yang Zhao","doi":"10.1007/s00018-025-05716-7","DOIUrl":"https://doi.org/10.1007/s00018-025-05716-7","url":null,"abstract":"<p><strong>Background: </strong>Chronic kidney disease (CKD) is a prevalent global health issue characterized by progressive renal dysfunction and fibrosis, often leading to end-stage renal failure. Renal fibrosis, a hallmark of CKD, is driven by complex immune responses, including macrophage polarization and inflammatory signaling pathways. Progranulin (PGRN), a glycoprotein involved in inflammation and tissue repair, has emerged as a key regulator in various fibrotic diseases. However, the precise role of PGRN in macrophage polarization and renal fibrosis in CKD remains unclear and warrants further investigation.</p><p><strong>Methods: </strong>Renal tissue samples from CKD patients and unilateral ureteral obstruction (UUO)-induced mice were analyzed using immunohistochemistry, immunofluorescence, Western blotting, and qRT-PCR to assess fibrosis, macrophage infiltration, and key markers of autophagy and inflammation. Recombinant PGRN (rPGRN) was administered in vivo to assess its effects on renal fibrosis, macrophage polarization, and autophagic flux. To evaluate the role of PGRN, PGRN knockout (PGRN^-/-) mice were also utilized. The effects of PGRN on autophagic flux and mitochondrial dynamics were studied using mCherry-GFP-LC3 dual-labeling, and macrophage polarization was analyzed by flow cytometry and cytokine profiling.</p><p><strong>Results: </strong>PGRN expression is significantly elevated in CKD patients and UUO mice and is associated with increased macrophage infiltration and renal fibrosis. rPGRN administration in vivo aggravated fibrosis and promoted M2 macrophage polarization. In contrast, PGRN^-/- mice showed reduced renal fibrosis, significantly reduced collagen deposition, and reduced expression of pro-fibrotic cytokines. In addition, the mitochondrial function of PGRN^-/- renal fibrosis mice was improved, the mtDNA content of mouse kidney tissue was increased, the results of electron microscopy showed that the mitochondrial structure was relatively normal, the mitochondrial biogenesis related genes PGC1α, TOMM20 and Fis1 were up-regulated, and the levels of MFN2 and Drp1 were significantly reduced. In addition, autophagy related gene LC3 was decreased and P62 protein level was increased in PGRN^-/- model mice. Mechanically, PGRN interacts with autophagy related proteins ATG5 and ATG12 to regulate autophagy flux through the PI3K-Akt signaling pathway and promote the polarization of M2 macrophages.</p><p><strong>Conclusion: </strong>PGRN plays a critical role in driving renal fibrosis by regulating macrophage polarization, autophagy, and mitochondrial dynamics. Our findings suggest that PGRN exacerbates CKD progression by promoting M2 macrophage polarization and disrupting autophagic processes, highlighting PGRN as a potential therapeutic target for the treatment of CKD and renal fibrosis.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"186"},"PeriodicalIF":6.2,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12037463/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143961392","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Restoration of Shal/K_V4 proteostasis and motor function in a Drosophila model of spinocerebellar ataxia type 19/22.","authors":"Cheng-Tsung Hsiao, Ssu-Ju Fu, Kai-Min Cheng, Hsiang Lo, Chih-Yung Tang, Chih-Chiang Chan, Chung-Jiuan Jeng","doi":"10.1007/s00018-025-05711-y","DOIUrl":"https://doi.org/10.1007/s00018-025-05711-y","url":null,"abstract":"<p><p>Loss-of-function mutations in the human KCND3 gene encoding K_V4.3 K⁺ channels are linked to the autosomal dominant neurodegenerative disease spinocerebellar ataxia type 19/22 (SCA19/22). Previous biophysical and biochemical analyses in vitro support the notion that the autosomal dominant inheritance pattern of SCA19/22 is associated with the dominant-negative effects of disease-causing K_V4.3 mutants on proteostasis of their wild-type (WT) counterpart. Herein we aimed to explore whether the disease-causing mutants might perturb protein expression of endogenous K_V4.3 channel in human cells, as well as contributing to in vivo pathomechanisms underlying motor impairments and neurodegeneration in an animal model of SCA19/22. Substantial reduction in human K_V4.3 protein level was validated in skin fibroblasts derived from heterozygous SCA19/22 patients. Genetic knockdown of endogenous Shal, the fly ortholog of human K_V4.3, in Drosophila led to locomotor impairment, ommatidia degeneration, and reduced brain cortex thickness, all of which was effectively ameliorated by transgenic expression of human K_V4.3, but not K_V1.1 K⁺ channel. Transgenic expression of SCA19/22-causing human K_V4.3 mutants resulted in notable disruption of endogenous Shal proteostasis, locomotor function, and ommatidia morphology in Drosophila. Enhanced expression of the Drosophila molecular chaperones HSC70 and HSP83 in our fly model of SCA19/22 corrected Shal protein deficit, locomotor dysfunction, and neurodegeneration. Overexpression of Hsp90β also upregulated endogenous human K_V4.3 protein level in patient-derived skin fibroblasts. Our findings highlight Drosophila as a suitable animal model for studying K_V4.3 channelopathy in vivo, and accentuate a critical role of defective K_V4.3 proteostasis in the pathogenesis of motor dysfunction and neurodegeneration in SCA19/22.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"181"},"PeriodicalIF":6.2,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12037467/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143963620","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Calciprotein particle-activated endothelial cells aggravate smooth muscle cell calcification via paracrine signalling.","authors":"Lian Feenstra, Lara W Zeper, Brenda van de Langenberg, Eveline J E M Kahlman, Guido de La Roij, Melanie Reijrink, Benoit Bernay, Laurent Chatre, Jeroen Kuipers, Ben N G Giepmans, Mirjam F Mastik, Wierd Kooistra, Monique E Lodewijk, Malou Zuidscherwoude, Robert A Pol, Edward R Smith, Guido Krenning, Jeroen H F de Baaij, Jan-Luuk Hillebrands, Joost G J Hoenderop","doi":"10.1007/s00018-025-05702-z","DOIUrl":"https://doi.org/10.1007/s00018-025-05702-z","url":null,"abstract":"<p><strong>Background: </strong>Vascular calcification is highly prevalent in Chronic Kidney Disease (CKD) and is associated with markedly increased cardiovascular risk. High serum phosphate in CKD increases calcification propensity via generation of circulating calciprotein particles (CPP2), crystalline nanoaggregates composed of calcium, phosphate, and serum proteins. CPP2 induce vascular calcification in vascular smooth muscle cells (VSMCs) in vitro. In vivo, endothelial cells, rather than VSMCs are primarily exposed to CPP2, yet understanding the influence of endothelial cells on vascular calcification is limited.</p><p><strong>Methods: </strong>We investigated calcification-promoting signalling by endothelial cells on VSMCs. Effects of CPP2 exposure to endothelial cells on CPP2 uptake, endothelial cell activation, and endothelial cell-derived secretome were studied. Effects of the secretome on VSMC calcification were investigated. Using NanoString nCounter analysis the effects of CPP2-activated endothelial cell-conditioned medium on VSMCs gene expression were mapped.</p><p><strong>Results: </strong>Endothelial cells internalise CPP2 and elevate ICAM-1, E-selectin, and VCAM-1-mRNA expression, indicating endothelial activation. VSMCs cultured in conditioned medium from CPP2-activated endothelial cells demonstrated enhanced calcification, suggesting that CPP2-activated endothelial cells release pro-calcifying soluble factors. Mass spectrometry was utilized to identify 1171 proteins in the CPP2-activated endothelial cells' secretome. Among these, 76 proteins were differentially expressed compared to control endothelial cells' secretome, including proteins related to blood vessel development, extracellular matrix remodelling, and oxidative stress-related processes. Finally, endothelial cell-derived paracrine factors present in conditioned medium enhanced mRNA-expression of calcification-related factors in VSMCs.</p><p><strong>Conclusions: </strong>CPP2-activated endothelial cells promote VSMC calcification via paracrine signalling. In response to these paracrine factors, VSMCs increase the expression of pro-calcification genes.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"177"},"PeriodicalIF":6.2,"publicationDate":"2025-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12033162/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143987444","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Vitamin D enhances the therapeutic effect of TNF-α antibodies through lipid metabolism in overweight IBD patients.","authors":"Wei Yu, Pengpeng Huang, Yanling Jin, Fang Wu, Cuiping Zhang, Lili Jing, Ying Chen, Han Xu, Jiapin Xiong, Rong Zhang, Ke Zhao, Xue Li","doi":"10.1007/s00018-025-05626-8","DOIUrl":"10.1007/s00018-025-05626-8","url":null,"abstract":"<p><p>The inhibitory effects of the tumor necrosis factor-α (TNF-α) antibody infliximab (IFX) on colitis are well established. Since IFX dosing is weight-based and associated with various side effects, there is a growing interest in identifying combination therapies that can enhance its efficacy, particularly in overweight inflammatory bowel disease (IBD) patients, to maximize the anti-inflammatory effect while minimizing the required dose. Our research revealed that overweight IBD patients present decreased vitamin D levels in the intestinal epithelium alongside elevated TNF-α levels. In mice fed a high-fat diet (HFD) for four weeks, treatment with the vitamin D analog palicalcitol (PAL) reduced lipid synthesis and TNF-α production in intestinal epithelial cells (IECs). In a 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced experimental colitis model, PAL treatment mitigated TNF-α-induced damage to the intestinal epithelial barrier and reduced the activation of Th1 and Th17 cells in the lamina propria, thereby reducing colitis development in HFD-fed mice. Notably, the combination of IFX and PAL was more effective than IFX alone in treating colitis in these mice. Overall, our findings suggest that vitamin D inhibits TNF-α production by reducing lipid synthesis in IECs, thereby enhancing IFX therapy in overweight IBD patients.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"176"},"PeriodicalIF":6.2,"publicationDate":"2025-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12033164/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143954861","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Proteomics-based characterization of ribosome heterogeneity in adult mouse organs.","authors":"Marie R Brunchault, Anne-Marie Hesse, Julia Schaeffer, Albrecht Fröhlich, Ana Saintpierre, Charlotte Decourt, Florence Combes, Homaira Nawabi, Yohann Couté, Stephane Belin","doi":"10.1007/s00018-025-05708-7","DOIUrl":"https://doi.org/10.1007/s00018-025-05708-7","url":null,"abstract":"<p><p>The translation process, leading to protein synthesis from mRNA, has been long thought to be invariable in all cellular organisms. Increasing evidence shows that it is finely regulated by variable features of the translation machinery. Notably, ribosomes, the functional units of protein synthesis, are suggested to display variations in their composition, depending on the developmental stage, cell type or physio-pathological context, thus hinting a new level of actionable regulation of gene expression. Yet, a comprehensive map of the heterogeneity of ribosome composition in ribosomal proteins (RPs) in different organs and tissues is not available. In this work, we explored tissue-specific ribosome heterogeneity using mass spectrometry-based quantitative proteomic characterization of ribosomal fractions purified from 14 adult mouse organs and tissues. We performed crossed clustering and statistical analyses of RP composition to highlight stable, variable and tissue-specific RPs across organs and tissues. Focusing on specific RPs, we validated their varying abundances using a targeted proteomic approach and western blot analyses, providing further insights into the tissue-specific ribosome RP signature. Finally, we investigated the origin of RP variations in ribosome fraction of the different tissues, by comparing RP relative amounts in our ribosomal proteomic dataset with their corresponding transcript abundances in three independent transcriptomic datasets. Interestingly, we found that, in some tissues, the RP abundance in purified ribosomes does not always correlate with the corresponding RP transcript level, arguing for a translational regulation of RP expression, and/or a regulated incorporation of RPs into ribosomes. Altogether, our data support the notion of a tissue-specific RP signature of ribosomes, which opens avenues to study how specific ribosomal composition provides an additional level of regulation to control gene expression in different tissues and organs.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"175"},"PeriodicalIF":6.2,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12022211/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143968750","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"circCEP70 encoded protein inhibits the progression of hepatocellular carcinoma.","authors":"Lian Li, Liangliang Xu, Wenwei Liao, Peng Wang, Mingqing Xu, Bo Li, Ming Zhang","doi":"10.1007/s00018-025-05651-7","DOIUrl":"https://doi.org/10.1007/s00018-025-05651-7","url":null,"abstract":"<p><p>Cirrhosis is closely related to hepatocellular carcinoma (HCC), however, the regulation of circular RNA (circRNA) in HCC with cirrhotic background has not yet been well illustrated. In this study, high throughput circRNA sequencing was applied to identified candidate circRNAs in HCC samples with cirrhotic background. The biological function of candidate circRNA was validated in both in vitro and in vivo settings. Additionally, Alphafold 3, mass spectrometry analysis and immunofluorescence were employed to investigate the underlying mechanisms involved. We found circCEP70 exhibited significantly higher expression levels in cirrhotic HCC samples and showed a positive correlation with improved prognosis. The RNA binding protein U2AF2 was found to suppress the expression of circCEP70 in cirrhosis patients. In vitro and in vivo experiments, including CCK-8, EdU, plate cloning, transwell, scratch, subcutaneous tumor formation, liver metastasis in situ, and lung metastasis assays confirmed the anti-carcinogenic effects. Mechanistically, circCEP70 encoded a novel protein named CEP70-160aa, which interacted with PKM2 and hindered its translocation into the nucleus. This interaction led to reduce STAT3 phosphorylation in the nucleus, thus inhibiting HCC proliferation and metastasis. In cirrhotic microenvironment, circCEP70 prevented HCC proliferation and metastasis through PKM2/STAT3 axis, and RNA binding protein U2AF2 could inhibit circCEP70 expression.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"174"},"PeriodicalIF":6.2,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12022199/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143992969","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multiple sclerosis: what have we learned and can we still learn from electron microscopy.","authors":"Wendy Oost, Jan F Meilof, Wia Baron","doi":"10.1007/s00018-025-05690-0","DOIUrl":"https://doi.org/10.1007/s00018-025-05690-0","url":null,"abstract":"<p><p>Multiple sclerosis (MS) is an inflammatory neurodegenerative disease marked by the formation of demyelinated lesions in the central nervous system. MS lesions can undergo remyelination, temporarily alleviating symptoms, but as the disease advances, remyelination becomes less effective. Beyond lesions, normal-appearing brain tissue exhibits subtle alterations, potentially indicating a broader, diffuse pathology and/or increased susceptibility to lesion formation. The pathology of MS varies between grey and white matter lesions and their normal-appearing regions, which most likely relates to their distinct cellular composition. Despite insights gained from MRI studies, serum and blood analyses, and post-mortem tissue examination, the molecular mechanisms driving MS lesion formation and persistent demyelination remain poorly understood. Exploring less conventional methods, such as electron microscopy (EM), may provide valuable new insights. EM offers detailed, nanometre-scale structural analysis that may enhance findings from immunohistochemistry and 'omics' approaches on MS brain tissue. Although earlier EM studies from before the 1990's provided some foundational data, advancements in EM technology now enable more comprehensive and detailed structural analysis. In this review we outline the pathogenesis of MS, summarize current knowledge of its ultrastructural features, and highlight how cutting-edge EM techniques could uncover new insights into pathological processes, including lesion formation, remyelination failure and diffuse pathology, which may aid therapeutic development.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"172"},"PeriodicalIF":6.2,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12018678/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143984178","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}