Disease Models & Mechanisms最新文献_第6页

Cell death analysis of inducible, titratable neurodegenerative disease models in zebrafish and human stem cell-derived retinal organoids. 斑马鱼和人类干细胞衍生视网膜类器官中诱导、可滴定的神经退行性疾病模型的细胞死亡分析。

IF 3.6 3区医学

Disease Models & Mechanisms Pub Date : 2026-07-01 Epub Date: 2026-07-24 DOI: 10.1242/dmm.052747

Anneliese Ceisel, Gianna Graziano, Kevin Emmerich, Xiangqian Shi, Tae-In Kam, Miguel Flores-Bellver, M Natalia Vergara, Silvia Aparicio-Domingo, Boris M Brenerman, Anne Vielle, Elsie M Williams, Abigail V Sharrock, Uche Onuchuwku, Georgina S Martinez, Lydia G Sanders, Uzoamaka Nwagbo, Beichen Wang, Huanhuan Xiao, Grant Kroeschell, Yiqi Gao, Daniel J Choe, Caroline E Clouatre, Diego Alfaro Carcoba, Barak Reibman, Catalina Rodriguez, Kevin Yang, Shreya Banerjee, Frazer Matthews, James H Thierer, Genevieve Stein-O'Brien, Ted M Dawson, Valina L Dawson, David F Ackerley, M Valeria Canto-Soler, Liyun Zhang, Jeff S Mumm

{"title":"Cell death analysis of inducible, titratable neurodegenerative disease models in zebrafish and human stem cell-derived retinal organoids.","authors":"Anneliese Ceisel, Gianna Graziano, Kevin Emmerich, Xiangqian Shi, Tae-In Kam, Miguel Flores-Bellver, M Natalia Vergara, Silvia Aparicio-Domingo, Boris M Brenerman, Anne Vielle, Elsie M Williams, Abigail V Sharrock, Uche Onuchuwku, Georgina S Martinez, Lydia G Sanders, Uzoamaka Nwagbo, Beichen Wang, Huanhuan Xiao, Grant Kroeschell, Yiqi Gao, Daniel J Choe, Caroline E Clouatre, Diego Alfaro Carcoba, Barak Reibman, Catalina Rodriguez, Kevin Yang, Shreya Banerjee, Frazer Matthews, James H Thierer, Genevieve Stein-O'Brien, Ted M Dawson, Valina L Dawson, David F Ackerley, M Valeria Canto-Soler, Liyun Zhang, Jeff S Mumm","doi":"10.1242/dmm.052747","DOIUrl":"10.1242/dmm.052747","url":null,"abstract":"Inducible disease models enable large-scale screening by providing control over pathology onset, such as cell death in neurodegenerative disease. The nitroreductase (NTR)/prodrug system of cell ablation has facilitated investigations of cell function and regeneration but has not been widely adopted as a disease modeling platform, perhaps owing to assumptions that the cell death mechanism(s) elicited is artificial in nature. Prior reports suggested that NTR/prodrug-mediated death occurred through apoptosis, necroptosis and/or parthanatos, which have all been implicated in neurodegenerative disease. To clarify this issue, we investigated the cell death pathway(s) elicited by the prodrug metronidazole (MTZ) with improved nitroreductase enzyme variants. We assessed the cell death pathway(s) elicited by NTR 2.0-expressing zebrafish retinal neurons using a transcriptomic analysis, chemical inhibitors and gene-targeting assays. NTR-H, a novel NTR variant, was tested - and found to be effective - in human stem cell-derived retinal organoids. Parthanatos was implicated across all conditions tested, while evidence of apoptosis was variable. As parthanatos is associated with neurodegeneration, our results support the use of the NTR/MTZ system to create inducible neurodegenerative models targeted to specific disease-relevant neuronal cell types.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":"19 7","pages":""},"PeriodicalIF":3.6,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13474575/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148583730","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

A Drosophila tumor model identifies a conserved Upd-JAK/STAT-Akh signaling axis associated with metabolic changes in cancer cachexia. 果蝇肿瘤模型鉴定出与癌症恶病质代谢变化相关的保守Upd-JAK/STAT-Akh信号轴。

IF 3.6 3区医学

Disease Models & Mechanisms Pub Date : 2026-07-01 Epub Date: 2026-06-16 DOI: 10.1242/dmm.052659

Kewei Yu, Gurpreet S Moroak, Esther M Verheyen

引用次数: 0

Loss of endogenous tau suppresses APOE4-induced patterned behavioral decline and axon dysmorphia in a model of Alzheimer's disease. 在秀丽隐杆线虫阿尔茨海默病模型中，内源性tau蛋白的缺失抑制apoe4诱导的模式行为下降和轴突畸形。

IF 3.6 3区医学

Disease Models & Mechanisms Pub Date : 2026-07-01 Epub Date: 2026-07-27 DOI: 10.1242/dmm.052469

Eric A Cardona, Chelsea J Webber, Zheng Wu, Blythe M Bolton, Elif Sarinay-Cenik, Jonathan T Pierce

{"title":"Loss of endogenous tau suppresses APOE4-induced patterned behavioral decline and axon dysmorphia in a model of Alzheimer's disease.","authors":"Eric A Cardona, Chelsea J Webber, Zheng Wu, Blythe M Bolton, Elif Sarinay-Cenik, Jonathan T Pierce","doi":"10.1242/dmm.052469","DOIUrl":"10.1242/dmm.052469","url":null,"abstract":"Alzheimer's disease (AD) causes a characteristic spatiotemporal pattern of neurodegeneration. The factors that account for this pattern of degeneration, including associated neuronal dysfunction and dysmorphia, are unclear. Previously, we generated a model of AD using the nematode Caenorhabditis elegans with the AD risk variant of apolipoprotein E (APOE4). We showed that the soma of HSN class neurons degenerate in early-adult animals. Here, we performed behavioral analyses to deduce the effect of APOE4 on the function of distinct neuronal circuits. We found evidence that APOE4 induces dysfunction of other neurons; this spatiotemporal pattern roughly correlates with endogenous levels of PTL-1, the C. elegans homolog of human MAPT, also known as tau. Moreover, deletion of ptl-1 suppressed defects in multiple behaviors, suggesting broad protective effects across the nervous system including the HSN neurons. Lastly, we showed that PTL-1 in the touch receptor neurons, in which PTL-1 is most abundant, contributes non-cell autonomously to age-related axon dysmorphia and dysfunction of the HSN neurons. Our results suggest that C. elegans provides a useful in vivo system to study how endogenous tau acts downstream of APOE4 to cause progressive, patterned neurodegenerative phenotypes.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13474567/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148216913","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

A model of free sialic acid storage disorder reveals hypomyelinating leukodystrophy and Purkinje cell degeneration. 游离唾液酸储存障碍小鼠模型：低髓鞘性白质营养不良和浦肯野细胞变性。

IF 3.6 3区医学

Disease Models & Mechanisms Pub Date : 2026-07-01 Epub Date: 2026-07-27 DOI: 10.1242/dmm.052652

Mary E Hackbarth, Mahin S Hossain, Marya S Sabir, Petcharat Leoyklang, Heidi Dorward, John Douglas Burke, Gene Elliot, Lisa Garrett, Patricia Zerfas, Danielle A Springer, Laura Pollard, Stephen Wincovitch, Marjan Huizing, William A Gahl, May Christine V Malicdan

{"title":"A model of free sialic acid storage disorder reveals hypomyelinating leukodystrophy and Purkinje cell degeneration.","authors":"Mary E Hackbarth, Mahin S Hossain, Marya S Sabir, Petcharat Leoyklang, Heidi Dorward, John Douglas Burke, Gene Elliot, Lisa Garrett, Patricia Zerfas, Danielle A Springer, Laura Pollard, Stephen Wincovitch, Marjan Huizing, William A Gahl, May Christine V Malicdan","doi":"10.1242/dmm.052652","DOIUrl":"10.1242/dmm.052652","url":null,"abstract":"Free sialic acid storage disorder (FSASD) is a rare, neurodegenerative, lysosomal storage disease caused by biallelic variants in SLC17A5, which encodes the lysosomal sialic acid exporter, sialin. Although clinical severity varies, all affected individuals exhibit progressive neurological decline and characteristic lysosomal and urinary accumulation of free sialic acid. No US Food and Drug Administration-approved therapies currently exist, and the molecular underpinnings of central nervous system (CNS) dysfunction remain poorly defined. To model the most prevalent FSASD-associated allele, we generated a Slc17a5R39C mouse model carrying the pathogenic p.Arg39Cys variant using CRISPR/Cpf1. Homozygous Slc17a5R39C/R39C mice recapitulated key features of FSASD, including biochemical accumulation of free sialic acid, ataxia, tremors, seizures and shortened lifespan. Neuropathological analyses revealed widespread CNS hypomyelination, with relatively preserved peripheral nervous system myelination, while transcriptomic profiling showed broad suppression of myelin-associated genes and a cerebellum-specific inflammatory signature. This was accompanied by pronounced astrogliosis, progressive Purkinje cell degeneration and elevated neurofilament proteins, including serum neurofilament light polypeptide. Altogether, the Slc17a5R39C/R39C model of FSASD provides critical insights into disease pathogenesis, highlights region-specific neurodegenerative vulnerabilities, and establishes a robust preclinical platform for mechanistic investigation and therapeutic development.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13474576/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148028060","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

Systemic and cardiac pathology induced by a clinically relevant USP8 activating mutation. 临床相关USP8激活突变引起的全身和心脏病理。

IF 3.6 3区医学

Disease Models & Mechanisms Pub Date : 2026-07-01 Epub Date: 2026-07-22 DOI: 10.1242/dmm.052695

Tamara González-Costa, Abel Galicia-Martín, Daniel Calle, Lorena Cussó, María Teresa Soto-Navarrete, Xiaoxi Luo, Lucía Méndez-Peralta, Joaquim Grego-Bessa, José Luis de la Pompa

{"title":"Systemic and cardiac pathology induced by a clinically relevant USP8 activating mutation.","authors":"Tamara González-Costa, Abel Galicia-Martín, Daniel Calle, Lorena Cussó, María Teresa Soto-Navarrete, Xiaoxi Luo, Lucía Méndez-Peralta, Joaquim Grego-Bessa, José Luis de la Pompa","doi":"10.1242/dmm.052695","DOIUrl":"10.1242/dmm.052695","url":null,"abstract":"Cushing's disease (CD), the most common endogenous Cushing's syndrome, is caused by activating mutations in the ubiquitin-specific protease 8 (USP8) gene. These mutations drive adrenocorticotropic hormone (ACTH)-secreting pituitary adenomas and hypercortisolism. Clinical manifestations include muscle weakness, osteopenia, cataracts and cardiovascular dysfunction. To investigate the pathogenic mechanisms of USP8 gain of function, we generated a conditional transgenic mouse model expressing human USP8 (referred to as hUSP8) carrying the most prevalent activating mutation in CD adenomas (p.S718del). Systemic expression of hUSP8S718del in mice induced diffuse corticotroph hyperplasia of ACTH+ cells, rather than pituitary microadenomas, and did not lead to hypercortisolemia. Despite preservation of the hypothalamic-pituitary-adrenal axis, transgenic mice developed skeletal muscle atrophy, bone abnormalities, corneal keratitis with cataracts and cardiac dysfunction. Notably, myocardial-specific expression of hUSP8S718del recapitulated cardiac defects seen in mice with ubiquitous expression, demonstrating the direct role of USP8 activation in the heart. These findings show that expression of a clinically relevant USP8 gain-of-function mutation in mice recapitulates key features of a USP8-associated syndrome. Our results reveal tissue-specific effects of USP8 beyond pituitary tumorigenesis and identify a direct contribution of USP8 activation to cardiac pathology.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":"19 7","pages":""},"PeriodicalIF":3.6,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13446564/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148548090","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

Functional characterization of furin-mediated lipoprotein lipase cleavage. 呋喃介导的脂蛋白脂肪酶裂解的功能表征。

IF 3.6 3区医学

Disease Models & Mechanisms Pub Date : 2026-07-01 Epub Date: 2026-07-06 DOI: 10.1242/dmm.052897

Ming Jing Wu, Chelsea Yang, Sirui Wu, Garth Devlin, Feng-Chang Lin, Aravind Asokan, Saskia B Neher

引用次数: 0

Cystic fibrosis: insights from zebrafish models. 囊性纤维化：斑马鱼模型的见解。

IF 3.6 3区医学

Disease Models & Mechanisms Pub Date : 2026-07-01 Epub Date: 2026-08-05 DOI: 10.1242/dmm.052856

Sarahdja Cornélie, Laure Yatime, Georges Lutfalla, Stephen A Renshaw, Audrey Bernut

{"title":"Cystic fibrosis: insights from zebrafish models.","authors":"Sarahdja Cornélie, Laure Yatime, Georges Lutfalla, Stephen A Renshaw, Audrey Bernut","doi":"10.1242/dmm.052856","DOIUrl":"10.1242/dmm.052856","url":null,"abstract":"Cystic fibrosis (CF) is a severe, life-limiting genetic disorder caused by mutations in the CFTR gene, which lead to defective epithelial ion transport, abnormally thick mucus and multi organ dysfunction, predominantly affecting the lungs, pancreas and digestive system. Despite significant advances in patient care, the complex interplay between CFTR dysfunction, chronic infection and persistent inflammation remains a major therapeutic challenge. In this context, animal models are indispensable for elucidating the cellular and molecular mechanisms underlying CF pathogenesis and accelerating drug discovery. Here, we review the relevance of the zebrafish (Danio rerio) as a powerful and complementary preclinical model for CF research. In particular, we highlight the unique advantages of zebrafish, including its highly conserved innate immune system and optical transparency, which together enable in vivo visualization of host immune responses under CF-like conditions at subcellular resolution. We further summarize how Cftr-deficient zebrafish models have provided key insights into the increased susceptibility to CF-relevant pathogens, disease mechanisms affecting the pancreas and the reproductive system, and the deleterious neutrophil-driven inflammation that characterizes CF. Finally, we discuss the potential of the zebrafish model for the identification and validation of novel therapeutic strategies to treat infectious and inflammatory lung pathology in CF, and outline future directions to expand its translational impact in CF research.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":"19 7","pages":""},"PeriodicalIF":3.6,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13488410/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148673273","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

Unique and overlapping behavioral effects of isoform-specific NRXN1 deletions. 亚型特异性NRXN1缺失的独特和重叠的行为影响。

IF 3.6 3区医学

Disease Models & Mechanisms Pub Date : 2026-07-01 Epub Date: 2026-07-23 DOI: 10.1242/dmm.052862

Amanda E Friedman, Michele Perni, Josephine Millard, Damjan Karanfilovski, Michael Granato, Philip D Campbell

{"title":"Unique and overlapping behavioral effects of isoform-specific NRXN1 deletions.","authors":"Amanda E Friedman, Michele Perni, Josephine Millard, Damjan Karanfilovski, Michael Granato, Philip D Campbell","doi":"10.1242/dmm.052862","DOIUrl":"10.1242/dmm.052862","url":null,"abstract":"Mutations in the human neurexin 1 (NRXN1) gene are associated with neurodevelopmental disorders including autism and schizophrenia. Vertebrate NRXN1 produces three major NRXN1 isoforms, referred to as α, β and γ. Human genetic data suggest that deletions located at the 5' region of the gene disrupting the α isoform associate mostly with clinical behavioral deficits. Yet, 3' deletions that disrupt multiple isoforms have also been identified in clinical cases. Whether deletions that selectively affect specific NRXN1 isoforms result in specific behavioral deficits remains unclear. Here, combining larval sensorimotor assays with a custom hands-free social preference assay developed for juvenile zebrafish, we show that zebrafish harboring Nrxn1 deletions that differentially encompass α, β and/or γ isoforms display both unique and overlapping locomotion, sensorimotor behavior, and social behavior deficits. Combined, our results strongly support a model by which domain-selective nrxn1 deletions predict behavioral phenotypes. Moreover, our results demonstrate compelling relationships between genotype and resulting behavioral phenotypes, providing functional insights into the complexity of NRXN1-associated neuropsychiatric behaviors.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13446563/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148257759","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

Clarifying Frizzled 2 function in development through genetically validated mouse models. 通过基因验证的小鼠模型阐明frizzled2在发育中的功能。

IF 3.6 3区医学

Disease Models & Mechanisms Pub Date : 2026-07-01 Epub Date: 2026-06-26 DOI: 10.1242/dmm.052410

Megan N Michalski, Cassandra R Diegel, Zhendong A Zhong, Maddison E Marshall, Gabrielle E Foxa Wiartalla, Payton D Stevens, Kelly Suino-Powell, Levi L Blazer, Jarrett J Adams, Karsten Melcher, Sachdev S Sidhu, Stephane Angers, Bart O Williams

{"title":"Clarifying Frizzled 2 function in development through genetically validated mouse models.","authors":"Megan N Michalski, Cassandra R Diegel, Zhendong A Zhong, Maddison E Marshall, Gabrielle E Foxa Wiartalla, Payton D Stevens, Kelly Suino-Powell, Levi L Blazer, Jarrett J Adams, Karsten Melcher, Sachdev S Sidhu, Stephane Angers, Bart O Williams","doi":"10.1242/dmm.052410","DOIUrl":"10.1242/dmm.052410","url":null,"abstract":"Wnt receptors of the Frizzled (Fzd) family are widely considered to exhibit substantial functional redundancy, complicating efforts to therapeutically target individual receptors. Fzd2 was believed to be functionally redundant with Fzd1 and Fzd7, based on previously published global knockout mouse studies. By contrast, homozygosity for a Fzd2 global knockout mouse allele developed by the International Mouse Phenotype Consortium (IMPC) has been reported to cause embryonic lethality, suggesting that Fzd2 is critical for early embryonic development. If global deletion of Fzd2 leads to early lethality, conditional deletion models are necessary to identify tissue-specific phenotypes. We found that a previously published Fzd2 conditional deletion model does not eliminate Fzd2. We have generated a new conditional model to address the contradictory previous studies and allow tissue-specific studies of Fzd2. We successfully inserted two loxP sites around the Fzd2 gene and confirmed that subsequent Cre-mediated recombination creates a Fzd2 null allele. Global deletion of Fzd2 in this model does not cause embryonic lethality while limb-specific deletion causes limb shortening. This work supports the hypothesis that Fzd2 regulates limb development and emphasizes the importance of thoroughly validating newly generated mouse models.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13446565/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148249557","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

Welcoming new Editors to Disease Models & Mechanisms. 欢迎疾病模型和机制的新编辑。

IF 3.6 3区医学

Disease Models & Mechanisms Pub Date : 2026-07-01 Epub Date: 2026-07-22 DOI: 10.1242/dmm.053105

Kirsty Hooper

引用次数: 0