Disease Models & Mechanisms最新文献_第5页

Evidence of neuronal DNA damage in the brains of patients with Rett syndrome. Rett患者大脑中神经元DNA损伤的证据。

IF 3.3 3区医学

Disease Models & Mechanisms Pub Date : 2025-08-01 Epub Date: 2025-09-01 DOI: 10.1242/dmm.052358

Abril Morales, Elena Korsakova, Niloufar Mansooralavi, Peter Soliman, Sarvin Jahanbani, Michelle L Olsen, Aparna Badhuri, William E Lowry

{"title":"Evidence of neuronal DNA damage in the brains of patients with Rett syndrome.","authors":"Abril Morales, Elena Korsakova, Niloufar Mansooralavi, Peter Soliman, Sarvin Jahanbani, Michelle L Olsen, Aparna Badhuri, William E Lowry","doi":"10.1242/dmm.052358","DOIUrl":"10.1242/dmm.052358","url":null,"abstract":"Rett syndrome is characterized by the postnatal loss of neurophysiological function and regression of childhood development. Because the syndrome is X linked, and males with MECP2 mutations generally do not survive birth, the study of this syndrome has been complicated by the fact that, in the female brain, a portion of neurons express wild-type MECP2, and another portion of neurons express a non-functional allele of MECP2. Here, we present an approach that enables transcriptional profiling of individual neurons and direct comparison of neurons that express functional MECP2 with those that have diminished MECP2 function. With this novel profiling approach, we found that mutant neurons from the brains of patients with Rett syndrome show patterns of defects in expression of synaptic and metabolic genes. A similar analysis of rat brain lacking MECP2 expression yielded similar patterns, suggesting that rat is a suitable in vivo model of Rett syndrome. These analyses also identified DNA damage and senescence transcriptional signatures specifically in MECP2-null neurons, suggesting a possible trigger of dysfunction in Rett syndrome. Together, these data highlight potentially defective molecular, physiological and metabolic pathways in brain neurons of patients with Rett syndrome.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12452059/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144752653","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

park+/+ and park-/- Drosophila have sexually dimorphic brain redox chemistry. 果蝇具有两性二态的脑氧化还原化学。

IF 3.3 3区医学

Disease Models & Mechanisms Pub Date : 2025-08-01 Epub Date: 2025-08-19 DOI: 10.1242/dmm.052250

Amber N Juba, Bobbi Stwalley, Tigran Margaryan, Riley Hamel, Amanda N Foley, T Bucky Jones, Artak Tovmasyan, Lori M Buhlman

{"title":"park+/+ and park-/- Drosophila have sexually dimorphic brain redox chemistry.","authors":"Amber N Juba, Bobbi Stwalley, Tigran Margaryan, Riley Hamel, Amanda N Foley, T Bucky Jones, Artak Tovmasyan, Lori M Buhlman","doi":"10.1242/dmm.052250","DOIUrl":"10.1242/dmm.052250","url":null,"abstract":"Sexual dimorphism in Parkinson's disease (PD) pathophysiology is poorly understood. Elucidating consequences of disease-causing mutations on brain redox chemistry may reveal therapeutic targets for all people with PD. We report that male Drosophila had increased hydrogen peroxide and glutathione (G-SH) redox disequilibrium in vulnerable dopaminergic neuron mitochondria. Levels of cysteine and oxidized cystine were decreased, with cysteine/cystine ratios (indicating less oxidative stress) and G-SH levels being elevated in parkin-null (park-/-) Drosophila brains, and more so in males. We report effects of parkin loss and sex on the levels of low-molecular-weight thiols involved in G-SH synthesis, providing clues as to mechanisms implicated in altered levels of brain G-SH, cysteine and cystine. Protein nitration was decreased in the brain of park-/- flies, especially in females, suggesting that decreased nitric oxide levels compensate for loss of parkin or lack of protective nitric oxide synthase activity. Our results imply that park-/- flies have elevated levels of G-SH that meet antioxidant demand in the absence of parkin in the whole brain, but not in vulnerable neurons. Identification of sexually dimorphic PD risk factors could inform symptom management and highlight sex-specific therapeutic strategies.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":"18 8","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12403524/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144871859","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

Multi-modal comparative phenotyping of knock-in mouse models of frontotemporal dementia/amyotrophic lateral sclerosis. 额颞叶痴呆/肌萎缩侧索硬化症敲入小鼠模型的多模态比较表型分析。

IF 3.3 3区医学

Disease Models & Mechanisms Pub Date : 2025-08-01 Epub Date: 2025-08-26 DOI: 10.1242/dmm.052324

Sevda Boyanova, Gareth Banks, Tatiana V Lipina, Rasneer Sonia Bains, Hamish Forrest, Michelle Stewart, Mireia Carcolé, Carmelo Milioto, Adrian M Isaacs, Sara E Wells, Frances K Wiseman

{"title":"Multi-modal comparative phenotyping of knock-in mouse models of frontotemporal dementia/amyotrophic lateral sclerosis.","authors":"Sevda Boyanova, Gareth Banks, Tatiana V Lipina, Rasneer Sonia Bains, Hamish Forrest, Michelle Stewart, Mireia Carcolé, Carmelo Milioto, Adrian M Isaacs, Sara E Wells, Frances K Wiseman","doi":"10.1242/dmm.052324","DOIUrl":"10.1242/dmm.052324","url":null,"abstract":"Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are progressive adult-onset neurodegenerative diseases with overlapping pathological and genetic origins. They are caused by multiple underlying mechanisms leading to a common collection of clinical features that occur in a spectrum. Here, we report side-by-side longitudinal behavioural, cognitive and sensory phenotyping of two mouse models of ALS/FTD, to determine which aspects of the disease they recapitulate. We used knock-in models, in which the endogenous mouse orthologues of the C9orf72 and TARDBP (encoding TDP-43) genes have been altered to model specific molecular aspects of ALS/FTD. We found that the C9orf72GR400/+ model exhibits age-related deficit in short-term memory and that parental genotype affects exploration activity in offspring. In the TardbpQ331K/Q331K model, we found age-related changes in weight, fat mass, locomotion and marble burying. In both models, we found no evidence of deficits in vision or olfactory habituation-dishabituation. These data provide new insight into genotype-phenotype relationships in these ALS/FTD mice, which can be used to inform model choice and experimental design in future research studies.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":"18 8","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12421800/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144945870","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

Lymphatic dysfunction correlates with inflammation in a mouse model of amyotrophic lateral sclerosis. SOD1-G93A肌萎缩性侧索硬化症小鼠模型淋巴功能障碍与炎症相关。

IF 3.3 3区医学

Disease Models & Mechanisms Pub Date : 2025-07-01 Epub Date: 2025-07-16 DOI: 10.1242/dmm.052148

Akshaya Narayanan, Bonnie L Seaberg, Andrew Buxton, Alexandra Vernino, Victoria E Williams, Anthony Matarazzo, Jeet Kekre, Bhuvaneshwaran Subramanian, Wei Wang, Joseph M Rutkowski, Michelle Hook, Dylan A McCreedy, Mariappan Muthuchamy, Mendell Rimer

{"title":"Lymphatic dysfunction correlates with inflammation in a mouse model of amyotrophic lateral sclerosis.","authors":"Akshaya Narayanan, Bonnie L Seaberg, Andrew Buxton, Alexandra Vernino, Victoria E Williams, Anthony Matarazzo, Jeet Kekre, Bhuvaneshwaran Subramanian, Wei Wang, Joseph M Rutkowski, Michelle Hook, Dylan A McCreedy, Mariappan Muthuchamy, Mendell Rimer","doi":"10.1242/dmm.052148","DOIUrl":"10.1242/dmm.052148","url":null,"abstract":"Amyotrophic lateral sclerosis (ALS) is a rapidly progressive, ultimately fatal neurodegenerative disease, without effective modifying treatments. It affects both lower and upper motor neurons, causing skeletal muscle denervation and paralysis. Regardless of the mechanisms that initiate and drive ALS, chronic neuroinflammation and systemic immune system activation play key roles in disease progression. The lymphatic system is a network of vessels and organs essential for immune surveillance, tissue fluid balance and lipid absorption, critical for the resolution and progression of inflammation in the periphery. Its recent rediscovery in the central nervous system raises the possibility of it playing similar roles in neurological and neurodegenerative diseases featuring prominent neuroinflammation, such as ALS. We hypothesized that the structure and function of lymphatics are compromised in the most widely used murine model of ALS, the SOD1-G93A mouse. We found that these mice exhibit lymph transport dysfunction, diminished intrinsic lymphatic vessel tonic and phasic contractions, and an association between inflammation and lymphatic marker upregulation, despite absence of major structural changes in lymphatic network coverage in key affected tissues in the disease, skeletal muscle and spinal cord.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12309905/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144539422","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

Lamin variants cause cardiac arrhythmogenicity in Drosophila. 纤层蛋白变异引起果蝇心律失常。

IF 3.3 3区医学

Disease Models & Mechanisms Pub Date : 2025-07-01 Epub Date: 2025-07-25 DOI: 10.1242/dmm.052424

Stan W van Wijk, Puck Vree, Fabries G Huiskes, Reinier L van der Palen, Aiste Liutkute, Niels Voigt, Lori L Wallrath, Bianca J J M Brundel

{"title":"Lamin variants cause cardiac arrhythmogenicity in Drosophila.","authors":"Stan W van Wijk, Puck Vree, Fabries G Huiskes, Reinier L van der Palen, Aiste Liutkute, Niels Voigt, Lori L Wallrath, Bianca J J M Brundel","doi":"10.1242/dmm.052424","DOIUrl":"10.1242/dmm.052424","url":null,"abstract":"Atrial fibrillation (AF), the most common progressive cardiac arrhythmia, is associated with serious complications such as stroke and heart failure. Although common risk factors underlie AF onset, in 15% of the affected population, AF may have a genetic cause. Here, we investigated how LMNA variants cause cardiac arrhythmicity. Drosophila melanogaster strains were generated possessing the analogous variants in the Drosophila orthologue of human lamin A/C (LMNA), Lamin C (LamC). Heart wall movements in prepupae were recorded before (BTP) and after (ATP) tachypacing. ATP, flies expressing wild-type LamC, and the variants ΔN and p.R205W showed a significant reduction in heart rate (HR), but the arrhythmia index (AI) was not affected, compared to BTP. By contrast, those expressing p.N210K and p.R264Q showed a significant reduction in HR and increased AI, compared to BTP. p.N210K- and p.R264Q-expressing prepupae showed contrasting effects after pharmacological intervention with microtubule stabilizer taxol. Taxol attenuated the arrhythmogenicity in p.N210K-expressing prepupae, but aggravated it in p.R264Q-expressing prepupae. These findings suggest that different lamin variants trigger distinct molecular pathways that drive arrhythmogenic effects in Drosophila.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12320974/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144552569","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

Modeling immunoglobulin light chain amyloidosis in Caenorhabditis elegans. 秀丽隐杆线虫免疫球蛋白轻链淀粉样变模型。

IF 3.3 3区医学

Disease Models & Mechanisms Pub Date : 2025-07-01 Epub Date: 2025-07-25 DOI: 10.1242/dmm.052230

Margherita Romeo, Maria Monica Barzago, Alessandro Corbelli, Silvia Maglioni, Natascia Ventura, Carmina Natale, Andrea Conz, Mario Salmona, Giovanni Palladini, Mario Nuvolone, Fabio Fiordaliso, Giampaolo Merlini, Luisa Diomede

{"title":"Modeling immunoglobulin light chain amyloidosis in Caenorhabditis elegans.","authors":"Margherita Romeo, Maria Monica Barzago, Alessandro Corbelli, Silvia Maglioni, Natascia Ventura, Carmina Natale, Andrea Conz, Mario Salmona, Giovanni Palladini, Mario Nuvolone, Fabio Fiordaliso, Giampaolo Merlini, Luisa Diomede","doi":"10.1242/dmm.052230","DOIUrl":"10.1242/dmm.052230","url":null,"abstract":"Cardiomyopathy determines the prognosis of patients with immunoglobulin light chain (AL) amyloidosis, a rare systemic disease caused by the misfolding and deposition of monoclonal light chains (LCs). The reasons underlying their cardiac tropism remain unknown, and an animal model recapitulating the main pathological features of AL amyloidosis is needed. Taking advantage of the similarities between the vertebrate cardiac muscle and Caenorhabditis elegans pharynx, we developed a new transgenic nematode expressing a human amyloidogenic λ LC, the sequence of which was deduced from a patient with AL amyloidosis with cardiac involvement (MNH). Strains expressing a non-amyloidogenic LC (MNM) or the empty vector only (MNV) were generated as controls. At variance with controls, LCs expressed in the body-wall muscle of MNH worms formed soluble dimeric assemblies, which could be secreted and reach different organs. Notably, MNH worms exerted a pharyngeal impairment resembling cardiac functional dysfunction in patients with AL amyloidosis, accompanied by increased radical oxygen species production and tissue ultrastructural damage. This new animal model could help to elucidate the mechanisms underlying the cardiac-specific toxicity occurring in AL amyloidosis, providing innovative insights into the pathophysiology.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":"18 7","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12320968/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144706689","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

Understanding Duchenne muscular dystrophy-associated brain pathology. 了解杜氏肌营养不良相关的脑部病理。

IF 3.3 3区医学

Disease Models & Mechanisms Pub Date : 2025-07-01 Epub Date: 2025-08-01 DOI: 10.1242/dmm.052302

Minou A T Verhaeg, Rosanne Govaarts, Maaike van Putten

{"title":"Understanding Duchenne muscular dystrophy-associated brain pathology.","authors":"Minou A T Verhaeg, Rosanne Govaarts, Maaike van Putten","doi":"10.1242/dmm.052302","DOIUrl":"10.1242/dmm.052302","url":null,"abstract":"The most common neuromuscular disorder, Duchenne muscular dystrophy (DMD), is caused by mutations in the DMD gene, resulting in a lack of dystrophin. In addition to severe and progressive muscle wasting, a subset of individuals with DMD experience, to largely varying extents, behavioural and cognitive deficits, including a lower IQ, and neurological comorbidities, such as autism spectrum disorder, obsessive compulsive disorder and attention deficit hyperactivity disorder. Neuroimaging studies in individuals with DMD have identified widespread pathology, including structural, physiological and connective alterations. DMD mouse models exhibit a number of DMD-associated behavioural traits, including anxiety, social deficits and learning disabilities, and have been used to investigate DMD brain pathology. Although there are currently no therapies to treat DMD brain pathology, genetic approaches are being developed to restore dystrophin expression. In particular, the exon skipping approach shows promise in ameliorating certain DMD-associated behavioural deficits in preclinical settings. However, the therapeutic potential of postnatal restoration of dystrophin isoforms involved in neurodevelopment is unknown. Furthermore, challenges such as low dystrophin restoration efficacy and translatability from DMD mouse models to the clinic remain to be addressed.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":"18 7","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12352290/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144759434","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

Murine cell lines with defined mutations model different histological subtypes of epithelial ovarian cancer. 具有明确突变的新型小鼠细胞系可模拟上皮性卵巢癌的不同组织学亚型。

IF 3.3 3区医学

Disease Models & Mechanisms Pub Date : 2025-07-01 Epub Date: 2025-07-28 DOI: 10.1242/dmm.052177

Lixin Zhang, Yusi Fang, Ibrahim Uygun, Danyang Li, Mary Strange, Syed K Zaidi, Wenjia Wang, Julia Knight, Mackenzy Radolec, Esther Elishaev, Joan F Brozick, Allison Edwards, George Tseng, Sandra Cascio, Ronald Buckanovich, Robert P Edwards, Anda M Vlad

{"title":"Murine cell lines with defined mutations model different histological subtypes of epithelial ovarian cancer.","authors":"Lixin Zhang, Yusi Fang, Ibrahim Uygun, Danyang Li, Mary Strange, Syed K Zaidi, Wenjia Wang, Julia Knight, Mackenzy Radolec, Esther Elishaev, Joan F Brozick, Allison Edwards, George Tseng, Sandra Cascio, Ronald Buckanovich, Robert P Edwards, Anda M Vlad","doi":"10.1242/dmm.052177","DOIUrl":"10.1242/dmm.052177","url":null,"abstract":"Preclinical modeling of epithelial ovarian cancer in immune-competent mice progressing to orthotopic, spontaneous tumors is challenging, requiring multiple genetic modifications in the host. Transplantable models using cell lines are easier to implement than spontaneous animal models, given that they reproduce the key disease characteristics. To create new in vivo ovarian tumor models, we generated 28 murine ovarian cancer cell lines with distinct genetic traits, such as deletion of Trp53, activation of KrasG12D, or deletion of Pten or KrasG12D/Pten-/- combination. Two distinct Trp53 null cell lines recapitulate high-grade serous histology when orthotopically injected into immune-competent, syngeneic hosts. Cells with Pten deletion trigger high-grade endometrioid tumors, and cells with dual KrasG12D activation and Pten deletion model carcinosarcoma. The cells express different tumor antigens, secrete varying levels of cytokines and chemokines, and trigger tumors with diverse inflammation profiles and various intratumoral T- and B-lymphocyte infiltration patterns. RNA-sequencing data from 16 cell lines reveal the gene expression profile across distinct models with different histotypes. This versatile collection of murine cell lines supports translationally relevant studies in ovarian cancer.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12352289/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144607726","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

HIV-1 Nef synergizes with APOL1-G1 to induce nephrocyte cell death in HIV-related kidney diseases. HIV-1 Nef与APOL1-G1协同诱导hiv相关肾脏疾病的肾细胞死亡

IF 3.3 3区医学

Disease Models & Mechanisms Pub Date : 2025-07-01 Epub Date: 2025-08-01 DOI: 10.1242/dmm.052178

Jun-Yi Zhu, Yulong Fu, Joyce van de Leemput, Jing Yu, Jinliang Li, Patricio E Ray, Zhe Han

{"title":"HIV-1 Nef synergizes with APOL1-G1 to induce nephrocyte cell death in HIV-related kidney diseases.","authors":"Jun-Yi Zhu, Yulong Fu, Joyce van de Leemput, Jing Yu, Jinliang Li, Patricio E Ray, Zhe Han","doi":"10.1242/dmm.052178","DOIUrl":"10.1242/dmm.052178","url":null,"abstract":"People carrying two APOL1 risk alleles (RA) - G1 or G2 - are at greater risk of developing human immunodeficiency virus (HIV)-associated nephropathy (HIVAN). However, it remains unclear whether the encoded protein(s) (APOL1-RA) and HIV-1 Nef interact to induce podocyte cell death. Here, we generated transgenic flies that express APOL1-G1 (derived from a child with HIVAN) and HIV-1 nef specifically in the nephrocytes, the fly equivalent of mammalian podocytes, and assessed their individual and combined effects on the nephrocyte filtration structure and function. We found that HIV-1 Nef acts in synergy with APOL1-G1, resulting in nephrocyte structural and functional defects, and that Nef exacerbates the organelle acidification defects and autophagy reduction induced by APOL1-G1. The synergy between HIV-1 Nef and APOL1-G1 is built on their joint effects on elevating endoplasmic reticulum (ER) stress, triggering nephrocyte dysfunction and, ultimately, cell death. Thus, we identified ER stress as the converging point for the synergy between HIV-1 Nef and APOL1-G1 in inducing nephrocyte cell death. Given the high similarity between Drosophila nephrocytes and human podocytes, our findings suggest ER stress as a new therapeutic target for HIV-1- and APOL1-associated nephropathies.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":"18 7","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12352291/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144759433","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

Global partnerships in rare disease research. 罕见病研究方面的全球伙伴关系。

IF 3.3 3区医学

Disease Models & Mechanisms Pub Date : 2025-07-01 Epub Date: 2025-07-28 DOI: 10.1242/dmm.052401

Sanja Rogic, Guillaume Poirier-Morency, Philip Hieter, Paul Pavlidis

{"title":"Global partnerships in rare disease research.","authors":"Sanja Rogic, Guillaume Poirier-Morency, Philip Hieter, Paul Pavlidis","doi":"10.1242/dmm.052401","DOIUrl":"10.1242/dmm.052401","url":null,"abstract":"Rare diseases collectively impact hundreds of millions worldwide, yet the genetic causes of many remain unknown or poorly understood. Model organisms (MOs) - such as yeast, fly, zebrafish and mouse - provide powerful experimental systems for functional validation of candidate genes and variants, elucidation of gene function and disease mechanisms, and identification of potential therapeutic targets and treatments. However, gaps persist between clinical gene discovery and MO-based research. The Canadian Rare Diseases: Models and Mechanisms (RDMM) Network was established in 2014 to address this gap by linking clinicians with MO researchers through a scientist registry and peer-reviewed funding process. Over the past decade, the RDMM Network has funded over 160 collaborative projects, enabled insights into numerous rare conditions, and led to sustained partnerships and external funding. The RDMM Registry software has been adopted internationally, forming a network of interoperable registries that enable cross-border collaborations and expand access to MO expertise worldwide. Going forward, the Canadian RDMM Network remains committed to sharing its tools, processes and experience to help establish new RDMM-like networks worldwide and invites the global research community to join efforts to accelerate rare disease research.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":"18 7","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12352283/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144728543","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