Andrea Parente , Luigi Borzacchiello , Marianna Giaccio , Martina Bamundo , Riccardo Rubino , Ludovica D'Auria , Antonio Monaco , Alessandro Fraldi
{"title":"星形胶质细胞A1表型的进行性激活是小胶质细胞-星形胶质细胞串扰的基础,并有助于神经性MPS的神经炎症","authors":"Andrea Parente , Luigi Borzacchiello , Marianna Giaccio , Martina Bamundo , Riccardo Rubino , Ludovica D'Auria , Antonio Monaco , Alessandro Fraldi","doi":"10.1016/j.ymgme.2025.109224","DOIUrl":null,"url":null,"abstract":"<div><div>Neuroinflammation underlies neurodegenerative processes in neuronopathic mucopolysaccharidoses (MPS), with innate immunity known to have a dominating role. Here, by studying mouse models of neuronopathic MPS, we found that the neurotoxic reactive astrocytes A1 are present in the brain of MPS mice and progressively increase with age. Such A1 phenotype is associated to activated microglia and to microglia-mediated release of a subset of specific cytokines involved in the A1 phenotype. Additionally, in the mouse model of MPS-IIIA, one of the most severe neuronopathic MPS in humans, we also found that neuroinflammation proceeded concomitantly with the activation of transglutaminase 2, a multifunctional enzyme involved in a variety of cellular processes, mostly in the microglia. Moreover, amyloid deposition appears to be associated to the maintenance of these processes, indeed, inhibiting amyloid deposition in MPS-IIIA mice reduced TG2 expression, microglia activation and the relative amount of astrocyte A1 phenotype. Our results shed light on the microglia-astroglia crosstalk in neuronopathic MPS and on its implication in neuroinflammation and neurodegeneration in MPS, thus also suggesting new therapeutic targets for these diseases.</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"146 1","pages":"Article 109224"},"PeriodicalIF":3.5000,"publicationDate":"2025-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Progressive activation of the astrocyte A1 phenotype underlies microglia-astroglia crosstalk and contributes to neuroinflammation in neuronopathic MPS\",\"authors\":\"Andrea Parente , Luigi Borzacchiello , Marianna Giaccio , Martina Bamundo , Riccardo Rubino , Ludovica D'Auria , Antonio Monaco , Alessandro Fraldi\",\"doi\":\"10.1016/j.ymgme.2025.109224\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><div>Neuroinflammation underlies neurodegenerative processes in neuronopathic mucopolysaccharidoses (MPS), with innate immunity known to have a dominating role. Here, by studying mouse models of neuronopathic MPS, we found that the neurotoxic reactive astrocytes A1 are present in the brain of MPS mice and progressively increase with age. Such A1 phenotype is associated to activated microglia and to microglia-mediated release of a subset of specific cytokines involved in the A1 phenotype. Additionally, in the mouse model of MPS-IIIA, one of the most severe neuronopathic MPS in humans, we also found that neuroinflammation proceeded concomitantly with the activation of transglutaminase 2, a multifunctional enzyme involved in a variety of cellular processes, mostly in the microglia. Moreover, amyloid deposition appears to be associated to the maintenance of these processes, indeed, inhibiting amyloid deposition in MPS-IIIA mice reduced TG2 expression, microglia activation and the relative amount of astrocyte A1 phenotype. Our results shed light on the microglia-astroglia crosstalk in neuronopathic MPS and on its implication in neuroinflammation and neurodegeneration in MPS, thus also suggesting new therapeutic targets for these diseases.</div></div>\",\"PeriodicalId\":18937,\"journal\":{\"name\":\"Molecular genetics and metabolism\",\"volume\":\"146 1\",\"pages\":\"Article 109224\"},\"PeriodicalIF\":3.5000,\"publicationDate\":\"2025-08-21\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Molecular genetics and metabolism\",\"FirstCategoryId\":\"99\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S109671922500215X\",\"RegionNum\":2,\"RegionCategory\":\"生物学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"ENDOCRINOLOGY & METABOLISM\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Molecular genetics and metabolism","FirstCategoryId":"99","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S109671922500215X","RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"ENDOCRINOLOGY & METABOLISM","Score":null,"Total":0}
Progressive activation of the astrocyte A1 phenotype underlies microglia-astroglia crosstalk and contributes to neuroinflammation in neuronopathic MPS
Neuroinflammation underlies neurodegenerative processes in neuronopathic mucopolysaccharidoses (MPS), with innate immunity known to have a dominating role. Here, by studying mouse models of neuronopathic MPS, we found that the neurotoxic reactive astrocytes A1 are present in the brain of MPS mice and progressively increase with age. Such A1 phenotype is associated to activated microglia and to microglia-mediated release of a subset of specific cytokines involved in the A1 phenotype. Additionally, in the mouse model of MPS-IIIA, one of the most severe neuronopathic MPS in humans, we also found that neuroinflammation proceeded concomitantly with the activation of transglutaminase 2, a multifunctional enzyme involved in a variety of cellular processes, mostly in the microglia. Moreover, amyloid deposition appears to be associated to the maintenance of these processes, indeed, inhibiting amyloid deposition in MPS-IIIA mice reduced TG2 expression, microglia activation and the relative amount of astrocyte A1 phenotype. Our results shed light on the microglia-astroglia crosstalk in neuronopathic MPS and on its implication in neuroinflammation and neurodegeneration in MPS, thus also suggesting new therapeutic targets for these diseases.
期刊介绍:
Molecular Genetics and Metabolism contributes to the understanding of the metabolic and molecular basis of disease. This peer reviewed journal publishes articles describing investigations that use the tools of biochemical genetics and molecular genetics for studies of normal and disease states in humans and animal models.