Disease Models & Mechanisms最新文献

Models and challenges for studying forever chemicals and their impact on human health. 永远研究化学物质及其对人类健康影响的模型和挑战。

IF 3.3 3区医学

Disease Models & Mechanisms Pub Date : 2025-11-01 Epub Date: 2025-10-17 DOI: 10.1242/dmm.052320

Jana Jass, Y Bezabhe, Majid Mustafa, Daniel Ragnvaldsson, Per-Erik Olsson

引用次数: 0

A novel murine model for sporadic, malignant peripheral nerve sheath tumors, driven by BrafV600E and Pten loss. BrafV600E和Pten缺失驱动的散发性恶性周围神经鞘肿瘤小鼠新模型

IF 3.3 3区医学

Disease Models & Mechanisms Pub Date : 2025-10-09 DOI: 10.1242/dmm.052471

Julien Debbache, Myriam Gwerder, Elisabeth Rushing, Lukas Sommer

引用次数: 0

SCYL1 deficiency in CALFAN syndrome is associated with ER stress and cell death. CALFAN综合征中SCYL1缺乏与内质网应激和细胞死亡有关。

IF 3.3 3区医学

Disease Models & Mechanisms Pub Date : 2025-10-08 DOI: 10.1242/dmm.052371

John Hellicar, Tal Dattner, Tian Sun, Lily Percival, Ruby Chrisp, Andrea Pietrobattista, Tomasz Witkos, Aleksander Mironov, Lina Leghlam, Carolin Jentsch, Stefan Koelker, Georg F Hoffmann, Christian Staufner, Wanjin Hong, Dominic Lenz, Martin Lowe

{"title":"SCYL1 deficiency in CALFAN syndrome is associated with ER stress and cell death.","authors":"John Hellicar, Tal Dattner, Tian Sun, Lily Percival, Ruby Chrisp, Andrea Pietrobattista, Tomasz Witkos, Aleksander Mironov, Lina Leghlam, Carolin Jentsch, Stefan Koelker, Georg F Hoffmann, Christian Staufner, Wanjin Hong, Dominic Lenz, Martin Lowe","doi":"10.1242/dmm.052371","DOIUrl":"https://doi.org/10.1242/dmm.052371","url":null,"abstract":"CALFAN syndrome is a rare genetic disorder affecting the nervous system and liver, with skeletal abnormalities also reported. It is caused by mutations in the gene encoding SCYL1, a ubiquitously expressed protein localized to the secretory pathway. SCYL1 interacts with trafficking components including ARF GTPases and the COPI vesicle coat complex and appears to function in retrograde secretory trafficking. Despite this knowledge, the mechanisms that underlie CALFAN pathology remain poorly understood. Here, using CALFAN patient and SCYL1 knockout fibroblasts we reveal an accumulation of the abundant secretory cargo procollagen type I in the endoplasmic reticulum (ER) upon SCYL1 deficiency. Surprisingly, we failed to observe procollagen-I trafficking defects in the SCYL1-deficient cells. Nevertheless, ER accumulation of procollagen-I correlated with ER distension and induction of ER stress in the patient fibroblasts, which also underwent increased cell death. The phenotypes were observed at elevated temperature, mimicking the induction of pathology under febrile conditions in CALFAN patients. Our data suggest that ER stress induction is a pathological mechanism in CALFAN syndrome, and that targeting this process may represent a therapeutic strategy.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145250307","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

BMP-dependent mobilization of fatty acid metabolism promotes Caenorhabditis elegans survival on a bacterial pathogen. 脂肪酸代谢的bmp依赖性动员促进秀丽隐杆线虫在细菌病原体上的生存。

IF 3.3 3区医学

Disease Models & Mechanisms Pub Date : 2025-10-06 DOI: 10.1242/dmm.052357

Katerina K Yamamoto, Margaret Wan, Rijul S Penkar, Cathy Savage-Dunn

{"title":"BMP-dependent mobilization of fatty acid metabolism promotes Caenorhabditis elegans survival on a bacterial pathogen.","authors":"Katerina K Yamamoto, Margaret Wan, Rijul S Penkar, Cathy Savage-Dunn","doi":"10.1242/dmm.052357","DOIUrl":"10.1242/dmm.052357","url":null,"abstract":"The Bone Morphogenetic Proteins (BMPs) are secreted peptide ligands of the Transforming Growth Factor beta (TGF-β) family, initially identified for their roles in development and differentiation across animal species. They are now increasingly recognized for their roles in physiology and infectious disease. In the nematode Caenorhabditis elegans, the BMP ligand DBL-1 controls fat metabolism and immune response, in addition to its roles in body size regulation and development. DBL-1 regulates classical aspects of innate immunity, including the induction of anti-microbial peptides. We theorized that BMP-dependent regulation of fat metabolism could also promote resilience against microbial pathogens. We found that exposure to a bacterial pathogen alters total fat stores, lipid droplet dynamics, and lipid metabolism gene expression in a BMP-dependent manner. We further showed that fatty acid desaturation plays a major role in survival on a bacterial pathogen, while fatty acid β-oxidation plays a more minor role. We conclude that C. elegans mobilizes fatty acid metabolism in response to pathogen exposure to promote survival. Our investigation provides a framework to study potential metabolic interventions that could support therapeutics that are complementary to antibiotic strategies.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145231620","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Truncated CD19 as a selection marker for the isolation of stem cell derived β-cells. 截断的CD19作为干细胞衍生β细胞分离的选择标记。

IF 3.3 3区医学

Disease Models & Mechanisms Pub Date : 2025-10-06 DOI: 10.1242/dmm.052376

Luo Ting Helen Huang, Raymond Jun-Rui Gao, Dahai Zhang, Cuilan Nian, Willem Martzke, A M James Shapiro, Tatsuya Kin, Yaser Tahamtani, Francis C Lynn

引用次数: 0

ETV1 is a key regulator of enteroendocrine PYY production. ETV1是肠内分泌PYY产生的关键调节因子。

IF 3.3 3区医学

Disease Models & Mechanisms Pub Date : 2025-10-06 DOI: 10.1242/dmm.052610

Astrid M Baattrup, Marianne Terndrup Pedersen, Stine L Hansen, Martti Maimets, Fiona Gribble, Frank Reimann, Kim B Jensen

{"title":"ETV1 is a key regulator of enteroendocrine PYY production.","authors":"Astrid M Baattrup, Marianne Terndrup Pedersen, Stine L Hansen, Martti Maimets, Fiona Gribble, Frank Reimann, Kim B Jensen","doi":"10.1242/dmm.052610","DOIUrl":"https://doi.org/10.1242/dmm.052610","url":null,"abstract":"Background The intestine constitutes the largest endocrine organ and is a rich source of hormones that regulate metabolism. Enteroendocrine cells (EECs) can be subtyped based on their secretion of specific hormones with L-cells being characterised by expression of glucagon-like peptide-1 (GLP-1) and peptide YY (PYY). Collectively, these hormones play important roles in appetite regulation, however, it is not known, how they are regulated transcriptionally. The ETS Variant Transcription Factor 1 (ETV1) is expressed by L-cells, but its function remains unknown. Methods We examined Etv1 expression in single-cell-RNA-sequencing (scRNA-seq) datasets from the mouse small intestine and from organoid cultures. To assess the functional role of ETV1 in EECs, ETV1 loss-of-function and overexpression experiments were performed in murine small intestinal organoids. Gene expression was subsequently assessed with qPCR and scRNA-seq. Results We confirmed that Etv1 is enriched in the L-cell lineage both in vivo and in organoid cultures. Furthermore, we find that mutations of ETV1 in organoids led to a decrease in Pyy expression levels with no effect on Gcg levels or on overall cell composition and organoid morphology. Moreover, overexpression of ETV1 led to a modest but specific increase in Pyy levels. Conclusions We identify ETV1 as a regulator of Pyy expression illustrating for the first time how specific hormone levels in the L-cell lineage are transcriptionally regulated.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145231704","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The transcriptome and secreted factors of the intervertebral discs in STZ-HFD Type 2 diabetic male mice reveal extensive inflammation. STZ-HFD型 2型糖尿病雄性小鼠椎间盘的转录组和分泌因子显示广泛的炎症。

IF 3.3 3区医学

Disease Models & Mechanisms Pub Date : 2025-10-06 DOI: 10.1242/dmm.052384

Christian E Gonzalez, Rachana S Vaidya, Sade W Clayton, Simon Y Tang

{"title":"The transcriptome and secreted factors of the intervertebral discs in STZ-HFD Type 2 diabetic male mice reveal extensive inflammation.","authors":"Christian E Gonzalez, Rachana S Vaidya, Sade W Clayton, Simon Y Tang","doi":"10.1242/dmm.052384","DOIUrl":"10.1242/dmm.052384","url":null,"abstract":"The chronic inflammation observed during type 2 diabetes (T2D) is associated with spinal pathologies, including intervertebral disc (IVD) degeneration and chronic spine pain. Despite the presence of confounding factors, such as obesity, studies have shown that after adjusting for age, body mass index, and genetics (e.g. twins), patients with T2D suffer from disproportionately more IVD degeneration and/or back pain. We hypothesize that chronic T2D fosters a proinflammatory microenvironment within the IVD that promotes degeneration and disrupts IVD homeostasis. To test this hypothesis, we evaluated two commonly used mouse models of T2D - the leptin-receptor deficient mouse (db/db) and the chronic high-fat diet in mice with impaired beta-cell function (STZ-HFD). Compared to their genetic controls-C57BL/6 wild-type mice for STZ-HFD and heterozygous littermates for db/db-STZ-HFD IVDs exhibited more severe degeneration and elevated chemokine expression profiles. RNA-seq further revealed extensive transcriptional dysregulation in STZ-HFD IVDs that was not observed in the db/db model. The STZ-HFD IVDs also expressed enzymes that enhanced production of glycolytic AGE precursors, impaired non-AGE DAMP pathways, and reduced suppressors of RAGE turnover. These results suggest that, under controlled genetic and environmental conditions, the STZ-HFD model more accurately reflect the multifactorial inflammatory milieu characteristic of T2D-induced IVD degeneration.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145231682","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

14-3-3θ Phosphorylation at S232 reduces its interactome and regulates axonal trafficking. 14-3-3θ S232磷酸化减少其相互作用组并调节轴突运输。

IF 3.3 3区医学

Disease Models & Mechanisms Pub Date : 2025-10-02 DOI: 10.1242/dmm.052405

F Sanders Pair, Rudradip Pattanayak, James A Mobley, Kyoko Kojima, Mary Gannon, Roschongporn Ekkatine, William J Stone, Kasandra Scholz, Talene A Yacoubian

{"title":"14-3-3θ Phosphorylation at S232 reduces its interactome and regulates axonal trafficking.","authors":"F Sanders Pair, Rudradip Pattanayak, James A Mobley, Kyoko Kojima, Mary Gannon, Roschongporn Ekkatine, William J Stone, Kasandra Scholz, Talene A Yacoubian","doi":"10.1242/dmm.052405","DOIUrl":"https://doi.org/10.1242/dmm.052405","url":null,"abstract":"14-3-3 proteins impact protein-protein interactions (PPIs) that regulate neuronal functions. The 14-3-3θ isoform is protective in Parkinson's disease (PD) and Dementia with Lewy Bodies (DLB) models. Human PD and DLB brains show increased 14-3-3θ phosphorylation at S232. To understand the impact of 14-3-3θ phosphorylation on brain PPIs, we performed affinity-purification mass spectrometry (AP-MS) using S232 phospho-mutant knock-in models. Proteins binding 14-3-3θ in Cre control cortical lysates were enriched in proteins involved in neuronal morphogenesis and microtubule dynamics. We found a dramatic decrease in proteins binding to 14-3-3θ in S232D mice compared to S232A mice. Axonal trafficking associated with these differentially binding proteins. Live imaging of acidic vesicles in axons revealed reduced net velocity in S232A and S232D neurons compared to Cre controls. In S232D neurons, this was due to a dramatic increase in vesicle pausing, while S232A neurons showed reduced segmental velocity, suggesting disrupted dynein motility. We conclude 14-3-3θ phosphorylation fine tunes axonal transport of acidic vesicles. Disruption of axonal transport with aberrant phosphorylation observed in PD and DLB could contribute to impaired clearance of aggregated proteins in these disorders.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145205866","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

HTRA1-dependent proteolysis induces age-related retinal degeneration and exacerbates choroidal neovascularization. htra1依赖性蛋白水解诱导年龄相关性视网膜变性并加剧脉络膜新生血管。

IF 3.3 3区医学

Disease Models & Mechanisms Pub Date : 2025-10-01 Epub Date: 2025-09-17 DOI: 10.1242/dmm.052253

Kenneth J Katschke, Tom Truong, Victoria Pham, Hongkang Xi, Wanjian Tang, Xiaowu Gu, Pooja Teotia, Jeffrey W Hofmann, Shawnta Y Chaney, Daniel Kirchhofer, Menno van Lookeren Campagne, Marion Jeanne

{"title":"HTRA1-dependent proteolysis induces age-related retinal degeneration and exacerbates choroidal neovascularization.","authors":"Kenneth J Katschke, Tom Truong, Victoria Pham, Hongkang Xi, Wanjian Tang, Xiaowu Gu, Pooja Teotia, Jeffrey W Hofmann, Shawnta Y Chaney, Daniel Kirchhofer, Menno van Lookeren Campagne, Marion Jeanne","doi":"10.1242/dmm.052253","DOIUrl":"10.1242/dmm.052253","url":null,"abstract":"Polymorphisms in the ARMS2/HTRA1 locus on chromosome 10 enhance the risk of geographic atrophy and macular neovascularization, the advanced forms of age-related macular degeneration (AMD). Although HTRA1 mutations have been associated with microvascular defects in the brain, it remains unclear whether changes in HTRA1 expression contribute to AMD pathophysiology. In this study, we showed that, in AMD donor eyes, HTRA1 protein accumulated around the retinal pigment epithelium (RPE)/photoreceptor lesions. We then demonstrated that overexpression of catalytically active, but not catalytically inactive, HTRA1 in RPE cells in mice induced age-dependent loss of photoreceptors, inflammation and a decline in photoreceptor functional responses. This retinal degeneration was not exacerbated when the mice were exposed to phototoxic stress in the constant light exposure preclinical model. However, mice overexpressing catalytically active HTRA1 had significant exacerbation of laser-induced choroidal neovascularization lesions. Finally, as substrate processing may define the molecular basis for HTRA1-induced retinal degeneration, we initiated a proteomics approach and identified the visual cycle key player RBP3 as a disease-relevant HTRA1 substrate in the retina.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12486214/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144945815","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}

引用次数: 0

Retinopathy-associated inosine monophosphate dehydrogenase 1 mutations cause metabolic and filament defects in cones. 视网膜病变相关的肌苷单磷酸脱氢酶1突变导致锥体代谢和纤维缺陷。

IF 3.3 3区医学

Disease Models & Mechanisms Pub Date : 2025-10-01 Epub Date: 2025-09-17 DOI: 10.1242/dmm.052389

Kaitlyn M Rutter, Michelle M Giarmarco, Vivian Truong, Yekai Wang, Mark Eminhizer, Yinxiao Xiang, Whitney M Cleghorn, Gardenia Sanchez, Anika L Burrell, Justin M Kollman, Jianhai Du, Susan E Brockerhoff

{"title":"Retinopathy-associated inosine monophosphate dehydrogenase 1 mutations cause metabolic and filament defects in cones.","authors":"Kaitlyn M Rutter, Michelle M Giarmarco, Vivian Truong, Yekai Wang, Mark Eminhizer, Yinxiao Xiang, Whitney M Cleghorn, Gardenia Sanchez, Anika L Burrell, Justin M Kollman, Jianhai Du, Susan E Brockerhoff","doi":"10.1242/dmm.052389","DOIUrl":"10.1242/dmm.052389","url":null,"abstract":"Dominant variants in inosine monophosphate dehydrogenase 1 (IMPDH1), a key enzyme in the de novo synthesis of purine bases, cause progressive photoreceptor death, leading to blindness. To investigate the cause of degeneration, we generated the first mutant IMPDH1 animal models and expressed mutant forms of impdh1a in zebrafish cone photoreceptors. Unlike cones expressing exogenous normal impdh1a, cones containing impdh1a with the K238E mutation degenerated. Cones expressing impdh1a with the D226N mutation did not show significant cone loss by 2 years. Steady-state and flux metabolomics in zebrafish retinas revealed no differences in glucose shunting to the pentose phosphate pathway, no change in AMP or GMP due to D226N expression, but reduced AMP/IMP and GMP/IMP in K238E-expressing cones. cGMP levels were normal in both mutant retinas. Further, pde6cw59; impdh1asa23234 double mutant cones were not rescued from degeneration. Both K238E and D226N mutant-containing proteins formed abnormally large mislocalized filaments, which could disrupt normal dynamic protein-protein interactions. Our work disproves the model of a hyperactive enzyme leading to elevated cGMP causing cell death and reveals new defects associated with IMPDH1 mutant expression.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12486205/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144871856","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}

引用次数: 0