Pub Date : 2025-01-01Epub Date: 2025-01-29DOI: 10.1242/dmm.050878
Nikola Srnic, Felix Westcott, Eleanor Caney, Leanne Hodson
The excessive accumulation of intrahepatic triglyceride (IHTG) in the liver is a risk factor for metabolic diseases, including type 2 diabetes and cardiovascular disease. IHTG can excessively accumulate owing to imbalances in the delivery, synthesis, storage and disposal of fat to, in and from the liver. Although obesity is strongly associated with IHTG accumulation, emerging evidence suggests that the composition of dietary fat, in addition to its quantity, plays a role in mediating IHTG accumulation. Evidence from human cross-sectional and interventional studies indicates that diets enriched with saturated fat compared to other fat types and carbohydrates produce divergent effects on IHTG content. However, the mechanistic reasons for these observations remain unknown. Given the challenges of investigating such mechanisms in humans, cellular models are needed that can recapitulate human hepatocyte fatty acid metabolism. Here, we review what is known from human studies about how dietary fat, its quantity and composition contribute to IHTG accumulation. We also explore the effects of fatty acid composition on hepatocellular fat metabolism from data generated in cellular models to help explain the divergences observed in in vivo studies.
{"title":"Dietary fat quantity and composition influence hepatic lipid metabolism and metabolic disease risk in humans.","authors":"Nikola Srnic, Felix Westcott, Eleanor Caney, Leanne Hodson","doi":"10.1242/dmm.050878","DOIUrl":"10.1242/dmm.050878","url":null,"abstract":"<p><p>The excessive accumulation of intrahepatic triglyceride (IHTG) in the liver is a risk factor for metabolic diseases, including type 2 diabetes and cardiovascular disease. IHTG can excessively accumulate owing to imbalances in the delivery, synthesis, storage and disposal of fat to, in and from the liver. Although obesity is strongly associated with IHTG accumulation, emerging evidence suggests that the composition of dietary fat, in addition to its quantity, plays a role in mediating IHTG accumulation. Evidence from human cross-sectional and interventional studies indicates that diets enriched with saturated fat compared to other fat types and carbohydrates produce divergent effects on IHTG content. However, the mechanistic reasons for these observations remain unknown. Given the challenges of investigating such mechanisms in humans, cellular models are needed that can recapitulate human hepatocyte fatty acid metabolism. Here, we review what is known from human studies about how dietary fat, its quantity and composition contribute to IHTG accumulation. We also explore the effects of fatty acid composition on hepatocellular fat metabolism from data generated in cellular models to help explain the divergences observed in in vivo studies.</p>","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":"18 1","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11810042/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143058214","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-01Epub Date: 2025-01-29DOI: 10.1242/dmm.050883
Haoyu Wu, Annie S P Yang, Suzan Stelloo, Floris J M Roos, René H M Te Morsche, Anne H Verkerk, Maria V Luna-Velez, Laura Wingens, Johannes H W de Wilt, Robert W Sauerwein, Klaas W Mulder, Simon J van Heeringen, Monique M A Verstegen, Luc J W van der Laan, Hendrik Marks, Richárd Bártfai
Hepatic organoid cultures are a powerful model to study liver development and diseases in vitro. However, hepatocyte-like cells differentiated from these organoids remain immature compared to primary human hepatocytes (PHHs), which are the benchmark in the field. Here, we applied integrative single-cell transcriptome and chromatin accessibility analysis to reveal gene regulatory mechanisms underlying these differences. We found that, in mature human hepatocytes, activator protein 1 (AP-1) factors co-occupy regulatory regions with hepatocyte-specific transcription factors, including HNF4A, suggesting their potential cooperation in governing hepatic gene expression. Comparative analysis identified distinct transcription factor sets that are specifically active in either PHHs or intrahepatic cholangiocyte organoid (ICO)-derived human hepatocytes. ELF3 was one of the factors uniquely expressed in ICO-derived hepatocytes, and its expression negatively correlated with hepatic marker gene expression. Functional analysis further revealed that ELF3 depletion increased the expression of key hepatic markers in ICO-derived hepatocytes. Our integrative analysis provides insights into the transcriptional regulatory networks of PHHs and hepatic organoids, thereby informing future strategies for developing improved hepatic models.
{"title":"Multi-omics analysis reveals distinct gene regulatory mechanisms between primary and organoid-derived human hepatocytes.","authors":"Haoyu Wu, Annie S P Yang, Suzan Stelloo, Floris J M Roos, René H M Te Morsche, Anne H Verkerk, Maria V Luna-Velez, Laura Wingens, Johannes H W de Wilt, Robert W Sauerwein, Klaas W Mulder, Simon J van Heeringen, Monique M A Verstegen, Luc J W van der Laan, Hendrik Marks, Richárd Bártfai","doi":"10.1242/dmm.050883","DOIUrl":"10.1242/dmm.050883","url":null,"abstract":"<p><p>Hepatic organoid cultures are a powerful model to study liver development and diseases in vitro. However, hepatocyte-like cells differentiated from these organoids remain immature compared to primary human hepatocytes (PHHs), which are the benchmark in the field. Here, we applied integrative single-cell transcriptome and chromatin accessibility analysis to reveal gene regulatory mechanisms underlying these differences. We found that, in mature human hepatocytes, activator protein 1 (AP-1) factors co-occupy regulatory regions with hepatocyte-specific transcription factors, including HNF4A, suggesting their potential cooperation in governing hepatic gene expression. Comparative analysis identified distinct transcription factor sets that are specifically active in either PHHs or intrahepatic cholangiocyte organoid (ICO)-derived human hepatocytes. ELF3 was one of the factors uniquely expressed in ICO-derived hepatocytes, and its expression negatively correlated with hepatic marker gene expression. Functional analysis further revealed that ELF3 depletion increased the expression of key hepatic markers in ICO-derived hepatocytes. Our integrative analysis provides insights into the transcriptional regulatory networks of PHHs and hepatic organoids, thereby informing future strategies for developing improved hepatic models.</p>","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":"18 1","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11810045/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143058234","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-01Epub Date: 2025-01-29DOI: 10.1242/dmm.052079
Lobna Elkhadragy, Maximillian J Carlino, Luke R Jordan, Thomas Pennix, Nahed Ismail, Grace Guzman, Jonathan P Samuelson, Lawrence B Schook, Kyle M Schachtschneider, Ron C Gaba
Hepatocellular carcinoma (HCC) is an aggressive disease with poor prognosis, necessitating preclinical models for evaluating novel therapies. Large-animal models are particularly valuable for assessing locoregional therapies, which are widely employed across HCC stages. This study aimed to develop a large-animal HCC model with tailored tumor mutations. The Oncopig, a genetically engineered pig with inducible TP53R167H and KRASG12D, was used in the study. Hepatocytes were isolated from Oncopigs and exposed to Cre recombinase in vitro to create HCC cells, and additional mutations were introduced by CRISPR/Cas9 knockout of PTEN and CDKN2A. These edits increased Oncopig HCC cell proliferation and migration. Autologous HCC cells with these CRISPR edits were implanted into Oncopigs using two approaches: ultrasound-guided percutaneous liver injections, which resulted in the development of localized intrahepatic masses, and portal vein injections, which led to multifocal tumors that regressed over time. Tumors developed by both approaches harbored PTEN and CDKN2A knockout mutations. This study demonstrates the feasibility of developing genetically tailored HCC tumors in Oncopigs using somatic cell CRISPR editing and autologous implantation, providing a valuable large-animal model for in vivo therapeutic assessment.
{"title":"Development of a genetically tailored implantation hepatocellular carcinoma model in Oncopigs by somatic cell CRISPR editing.","authors":"Lobna Elkhadragy, Maximillian J Carlino, Luke R Jordan, Thomas Pennix, Nahed Ismail, Grace Guzman, Jonathan P Samuelson, Lawrence B Schook, Kyle M Schachtschneider, Ron C Gaba","doi":"10.1242/dmm.052079","DOIUrl":"10.1242/dmm.052079","url":null,"abstract":"<p><p>Hepatocellular carcinoma (HCC) is an aggressive disease with poor prognosis, necessitating preclinical models for evaluating novel therapies. Large-animal models are particularly valuable for assessing locoregional therapies, which are widely employed across HCC stages. This study aimed to develop a large-animal HCC model with tailored tumor mutations. The Oncopig, a genetically engineered pig with inducible TP53R167H and KRASG12D, was used in the study. Hepatocytes were isolated from Oncopigs and exposed to Cre recombinase in vitro to create HCC cells, and additional mutations were introduced by CRISPR/Cas9 knockout of PTEN and CDKN2A. These edits increased Oncopig HCC cell proliferation and migration. Autologous HCC cells with these CRISPR edits were implanted into Oncopigs using two approaches: ultrasound-guided percutaneous liver injections, which resulted in the development of localized intrahepatic masses, and portal vein injections, which led to multifocal tumors that regressed over time. Tumors developed by both approaches harbored PTEN and CDKN2A knockout mutations. This study demonstrates the feasibility of developing genetically tailored HCC tumors in Oncopigs using somatic cell CRISPR editing and autologous implantation, providing a valuable large-animal model for in vivo therapeutic assessment.</p>","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11810043/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142946261","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-01Epub Date: 2025-01-10DOI: 10.1242/dmm.052052
John J Willoughby, Abbie M Jensen
Stargardt disease (STGD), the leading cause of inherited childhood blindness, is primarily caused by mutations in the ABCA4 gene; yet, the underlying mechanisms of photoreceptor degeneration remain elusive, partly due to limitations in existing animal disease models. To expand our understanding, we mutated the human ABCA4 paralogues abca4a and abca4b in zebrafish, which has a cone-rich retina. Our study unveiled striking dysmorphology and elongation of cone outer segments (COS) in abca4a;abca4b double mutants, alongside reduced phagocytosis by the retinal pigmented epithelium (RPE). We report that zebrafish Abca4 protein forms a distinctive stripe along the length of COS, suggesting a potential structural role. We further show that, in wild-type zebrafish, outer segments of cone cells constitutively present externalized phosphatidylserine, an apoptotic 'eat-me' signal, and that this pattern is disrupted in abca4a;abca4b double mutants, potentially contributing to reduced RPE phagocytic activity. More broadly, constitutive presentation of the 'eat-me' signal by COS - if conserved in humans - might have important implications for other retinal degenerative diseases, including age-related macular degeneration. Our zebrafish model provides novel insights into cone dysfunction and presents a promising platform for unraveling the mechanisms of STGD pathogenesis and advancing therapeutic interventions.
{"title":"Abca4, mutated in Stargardt disease, is required for structural integrity of cone outer segments.","authors":"John J Willoughby, Abbie M Jensen","doi":"10.1242/dmm.052052","DOIUrl":"10.1242/dmm.052052","url":null,"abstract":"<p><p>Stargardt disease (STGD), the leading cause of inherited childhood blindness, is primarily caused by mutations in the ABCA4 gene; yet, the underlying mechanisms of photoreceptor degeneration remain elusive, partly due to limitations in existing animal disease models. To expand our understanding, we mutated the human ABCA4 paralogues abca4a and abca4b in zebrafish, which has a cone-rich retina. Our study unveiled striking dysmorphology and elongation of cone outer segments (COS) in abca4a;abca4b double mutants, alongside reduced phagocytosis by the retinal pigmented epithelium (RPE). We report that zebrafish Abca4 protein forms a distinctive stripe along the length of COS, suggesting a potential structural role. We further show that, in wild-type zebrafish, outer segments of cone cells constitutively present externalized phosphatidylserine, an apoptotic 'eat-me' signal, and that this pattern is disrupted in abca4a;abca4b double mutants, potentially contributing to reduced RPE phagocytic activity. More broadly, constitutive presentation of the 'eat-me' signal by COS - if conserved in humans - might have important implications for other retinal degenerative diseases, including age-related macular degeneration. Our zebrafish model provides novel insights into cone dysfunction and presents a promising platform for unraveling the mechanisms of STGD pathogenesis and advancing therapeutic interventions.</p>","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11744051/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142750223","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The sulfate transporter gene SLC26A2 is crucial for skeletal formation, as evidenced by its role in diastrophic dysplasia, a type of skeletal dysplasia in humans. Although SLC26A2-related chondrodysplasia also affects craniofacial and tooth development, its specific role in these processes remains unclear. In this study, we explored the pivotal roles of SLC26A2-mediated sulfate metabolism during tooth development. We found that Slc26a2 was predominantly expressed in dental tissues, including odontoblasts and ameloblasts. Slc26a2 knockout (Slc26a2-KO-Δexon2) mice exhibited distinct craniofacial abnormalities, such as a retrognathic upper jaw, small upper incisors and upper molar hypoplasia. These mice also showed flattened odontoblasts and loss of nuclear polarity in upper incisors and molars, with significant reductions in odontoblast differentiation markers Dspp and Dmp1. Ex vivo and in vitro studies further revealed dentin matrix hypoplasia, tooth root shortening and downregulation of Wnt signaling in Slc26a2-deficient cells. These findings highlight the crucial role of SLC26A2-mediated sulfate metabolism in tooth development and offer insights into the mechanisms underlying dental abnormalities in patients with SLC26A2-related chondrodysplasias.
{"title":"Slc26a2-mediated sulfate metabolism is important in tooth development.","authors":"Yuka Yoshida, Toshihiro Inubushi, Mika Yokoyama, Priyanka Nag, Jun-Ichi Sasaki, Ayaka Oka, Tomoya Murotani, Renshiro Kani, Yuki Shiraishi, Hiroshi Kurosaka, Yoshifumi Takahata, Riko Nishimura, Satoshi Imazato, Petros Papagerakis, Takashi Yamashiro","doi":"10.1242/dmm.052107","DOIUrl":"10.1242/dmm.052107","url":null,"abstract":"<p><p>The sulfate transporter gene SLC26A2 is crucial for skeletal formation, as evidenced by its role in diastrophic dysplasia, a type of skeletal dysplasia in humans. Although SLC26A2-related chondrodysplasia also affects craniofacial and tooth development, its specific role in these processes remains unclear. In this study, we explored the pivotal roles of SLC26A2-mediated sulfate metabolism during tooth development. We found that Slc26a2 was predominantly expressed in dental tissues, including odontoblasts and ameloblasts. Slc26a2 knockout (Slc26a2-KO-Δexon2) mice exhibited distinct craniofacial abnormalities, such as a retrognathic upper jaw, small upper incisors and upper molar hypoplasia. These mice also showed flattened odontoblasts and loss of nuclear polarity in upper incisors and molars, with significant reductions in odontoblast differentiation markers Dspp and Dmp1. Ex vivo and in vitro studies further revealed dentin matrix hypoplasia, tooth root shortening and downregulation of Wnt signaling in Slc26a2-deficient cells. These findings highlight the crucial role of SLC26A2-mediated sulfate metabolism in tooth development and offer insights into the mechanisms underlying dental abnormalities in patients with SLC26A2-related chondrodysplasias.</p>","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11655027/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142603132","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-01Epub Date: 2024-12-16DOI: 10.1242/dmm.052218
Ivan Molotkov, Elaine R Mardis, Mykyta Artomov
Computational tools for predicting variant pathogenicity are widely used to support clinical variant interpretation. Recently, several models, which do not rely on known variant classifications during training, have been developed. These approaches can potentially overcome biases of current clinical databases, such as misclassifications, and can potentially better generalize to novel, unclassified variants. AlphaMissense is one such model, built on the highly successful protein structure prediction model, AlphaFold. AlphaMissense has shown great performance in benchmarks of functional and clinical data, outperforming many supervised models that were trained on similar data. However, like other in silico predictors, AlphaMissense has notable limitations. As a large deep learning model, it lacks interpretability, does not assess the functional impact of variants, and provides pathogenicity scores that are not disease specific. Improving interpretability and precision in computational tools for variant interpretation remains a promising area for advancing clinical genetics.
{"title":"Making sense of missense: challenges and opportunities in variant pathogenicity prediction.","authors":"Ivan Molotkov, Elaine R Mardis, Mykyta Artomov","doi":"10.1242/dmm.052218","DOIUrl":"10.1242/dmm.052218","url":null,"abstract":"<p><p>Computational tools for predicting variant pathogenicity are widely used to support clinical variant interpretation. Recently, several models, which do not rely on known variant classifications during training, have been developed. These approaches can potentially overcome biases of current clinical databases, such as misclassifications, and can potentially better generalize to novel, unclassified variants. AlphaMissense is one such model, built on the highly successful protein structure prediction model, AlphaFold. AlphaMissense has shown great performance in benchmarks of functional and clinical data, outperforming many supervised models that were trained on similar data. However, like other in silico predictors, AlphaMissense has notable limitations. As a large deep learning model, it lacks interpretability, does not assess the functional impact of variants, and provides pathogenicity scores that are not disease specific. Improving interpretability and precision in computational tools for variant interpretation remains a promising area for advancing clinical genetics.</p>","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":"17 12","pages":""},"PeriodicalIF":4.0,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11683568/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142827905","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-01Epub Date: 2024-12-13DOI: 10.1242/dmm.050716
Mireia Sueca-Comes, Elena Cristina Rusu, Jennifer C Ashworth, Pamela Collier, Catherine Probert, Alison Ritchie, Marian Meakin, Nigel P Mongan, Isioma U Egbuniwe, Jesper Bøje Andersen, David O Bates, Anna M Grabowska
The tumour microenvironment (TME) significantly influences tumour formation and progression through dynamic interactions. Cholangiocarcinoma (CCA), a highly desmoplastic tumour, lacks early diagnostic biomarkers and has limited effective treatments owing to incomplete understanding of its molecular pathogenesis. Investigating the role of the TME in CCA progression could lead to better therapies. RNA sequencing was performed on seven CCA patient-derived xenografts (PDXs) and their corresponding patient samples. Differential expression analysis was conducted, and Qiagen Ingenuity Pathway Analysis was used to predict dysregulated pathways and upstream regulators. PDX- and cell line-derived spheroids, with and without immortalised mesenchymal stem cells, were grown and analysed for morphology, growth and viability. Histological analysis confirmed biliary phenotypes. RNA sequencing indicated upregulation of extracellular matrix-receptor interaction and PI3K-AKT pathways in the presence of mesenchymal cells, with several genes linked to poor survival. Mesenchymal cells restored the activity of inhibited cancer-associated kinases. Thus, adding mesenchymal cells to CCA spheroid models restored key paracrine signalling pathways lost in PDXs, enhancing tumour growth and viability. These findings highlight the importance of including stromal components in cancer models to improve pre-clinical studies.
{"title":"The role of mesenchymal cells in cholangiocarcinoma.","authors":"Mireia Sueca-Comes, Elena Cristina Rusu, Jennifer C Ashworth, Pamela Collier, Catherine Probert, Alison Ritchie, Marian Meakin, Nigel P Mongan, Isioma U Egbuniwe, Jesper Bøje Andersen, David O Bates, Anna M Grabowska","doi":"10.1242/dmm.050716","DOIUrl":"10.1242/dmm.050716","url":null,"abstract":"<p><p>The tumour microenvironment (TME) significantly influences tumour formation and progression through dynamic interactions. Cholangiocarcinoma (CCA), a highly desmoplastic tumour, lacks early diagnostic biomarkers and has limited effective treatments owing to incomplete understanding of its molecular pathogenesis. Investigating the role of the TME in CCA progression could lead to better therapies. RNA sequencing was performed on seven CCA patient-derived xenografts (PDXs) and their corresponding patient samples. Differential expression analysis was conducted, and Qiagen Ingenuity Pathway Analysis was used to predict dysregulated pathways and upstream regulators. PDX- and cell line-derived spheroids, with and without immortalised mesenchymal stem cells, were grown and analysed for morphology, growth and viability. Histological analysis confirmed biliary phenotypes. RNA sequencing indicated upregulation of extracellular matrix-receptor interaction and PI3K-AKT pathways in the presence of mesenchymal cells, with several genes linked to poor survival. Mesenchymal cells restored the activity of inhibited cancer-associated kinases. Thus, adding mesenchymal cells to CCA spheroid models restored key paracrine signalling pathways lost in PDXs, enhancing tumour growth and viability. These findings highlight the importance of including stromal components in cancer models to improve pre-clinical studies.</p>","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11655028/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142567801","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-01Epub Date: 2024-12-06DOI: 10.1242/dmm.052011
Sahiba Siddiqui, Fang Liu, Anumantha G Kanthasamy, Maura McGrail
The Alzheimer's disease and Parkinson's disease risk locus FYN kinase is implicated in neurodegeneration and inflammatory signaling. To investigate in vivo mechanisms of Fyn-driven neurodegeneration, we built a zebrafish neural-specific Gal4:UAS model of constitutively active FynY531F signaling. Using in vivo live imaging, we demonstrated that neural FynY531F expression leads to dopaminergic neuron loss and mitochondrial aggregation in 5 day larval brain. Dopaminergic loss coincided with microglia activation and induction of tnfa, il1b and il12a inflammatory cytokine expression. Transcriptome analysis revealed Stat3 signaling as a potential Fyn target. Chemical inhibition experiments confirmed Fyn-driven dopaminergic neuron loss, and the inflammatory response was dependent upon activation of Stat3 and NF-κB pathways. Dual chemical inhibition demonstrated that Stat3 acts synergistically with NF-κB in dopaminergic neuron degeneration. These results identify Stat3 as a novel downstream effector of Fyn signaling in neurodegeneration and inflammation.
{"title":"Stat3 mediates Fyn kinase-driven dopaminergic neurodegeneration and microglia activation.","authors":"Sahiba Siddiqui, Fang Liu, Anumantha G Kanthasamy, Maura McGrail","doi":"10.1242/dmm.052011","DOIUrl":"10.1242/dmm.052011","url":null,"abstract":"<p><p>The Alzheimer's disease and Parkinson's disease risk locus FYN kinase is implicated in neurodegeneration and inflammatory signaling. To investigate in vivo mechanisms of Fyn-driven neurodegeneration, we built a zebrafish neural-specific Gal4:UAS model of constitutively active FynY531F signaling. Using in vivo live imaging, we demonstrated that neural FynY531F expression leads to dopaminergic neuron loss and mitochondrial aggregation in 5 day larval brain. Dopaminergic loss coincided with microglia activation and induction of tnfa, il1b and il12a inflammatory cytokine expression. Transcriptome analysis revealed Stat3 signaling as a potential Fyn target. Chemical inhibition experiments confirmed Fyn-driven dopaminergic neuron loss, and the inflammatory response was dependent upon activation of Stat3 and NF-κB pathways. Dual chemical inhibition demonstrated that Stat3 acts synergistically with NF-κB in dopaminergic neuron degeneration. These results identify Stat3 as a novel downstream effector of Fyn signaling in neurodegeneration and inflammation.</p>","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":"17 12","pages":""},"PeriodicalIF":4.0,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11646115/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142784486","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-01Epub Date: 2024-12-24DOI: 10.1242/dmm.052202
Bettina Ryll
{"title":"Scaling up the impact of melanoma advocacy: an interview with Bettina Ryll.","authors":"Bettina Ryll","doi":"10.1242/dmm.052202","DOIUrl":"10.1242/dmm.052202","url":null,"abstract":"","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":"17 12","pages":""},"PeriodicalIF":4.0,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11698029/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142881437","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Variants in several genes are linked to human frontotemporal lobar degeneration (FTLD) associated with TDP43- and/or ubiquitin-positive inclusions. However, it is not yet clear whether the underlying mechanism is a gain-of-function or a loss-of-function one. To answer this question, we used Drosophila expressing double-stranded RNA against the FTLD-associated gene TER94 (an ortholog of VCP/p97) and found that the knockdown (KD) of this gene caused premature lethality, reduction in brain volume and alterations in the morphology of mushroom bodies. The changes caused by TER94 KD were rescued by wild-type TER94 but not by the human disease-linked A229E mutant, indicating that this mutant causes loss of function. Alterations were also observed in pupal brains and were partially rescued by co-expression of Mcm2, which is involved in control of the cell cycle, suggesting that dysregulation of neuronal proliferation caused the phenotypes. TER94 KD also caused the disappearance of TBPH (an ortholog of TDP43/TARDBP) from nuclei. These data from Drosophila genetics suggest that VCP-linked FTLD is caused by loss-of-function of VCP.
{"title":"Loss of function of VCP/TER94 causes neurodegeneration.","authors":"Kohei Tsumaki, Christian J F Bertens, Minoru Nakayama, Saya Kato, Yuki Jonao, Ayu Kuribayashi, Konosuke Sato, Shota Ishiyama, Momoko Asakawa, Riko Aihara, Yuki Yoshioka, Hidenori Homma, Hikari Tanaka, Kyota Fujita, Hitoshi Okazawa, Masaki Sone","doi":"10.1242/dmm.050359","DOIUrl":"10.1242/dmm.050359","url":null,"abstract":"<p><p>Variants in several genes are linked to human frontotemporal lobar degeneration (FTLD) associated with TDP43- and/or ubiquitin-positive inclusions. However, it is not yet clear whether the underlying mechanism is a gain-of-function or a loss-of-function one. To answer this question, we used Drosophila expressing double-stranded RNA against the FTLD-associated gene TER94 (an ortholog of VCP/p97) and found that the knockdown (KD) of this gene caused premature lethality, reduction in brain volume and alterations in the morphology of mushroom bodies. The changes caused by TER94 KD were rescued by wild-type TER94 but not by the human disease-linked A229E mutant, indicating that this mutant causes loss of function. Alterations were also observed in pupal brains and were partially rescued by co-expression of Mcm2, which is involved in control of the cell cycle, suggesting that dysregulation of neuronal proliferation caused the phenotypes. TER94 KD also caused the disappearance of TBPH (an ortholog of TDP43/TARDBP) from nuclei. These data from Drosophila genetics suggest that VCP-linked FTLD is caused by loss-of-function of VCP.</p>","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11698056/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142767167","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}