EMBO Molecular Medicine最新文献_第6页

ERK5 suppression overcomes FAK inhibitor resistance in mutant KRAS-driven non-small cell lung cancer. 抑制 ERK5 可克服突变 KRAS 驱动的非小细胞肺癌对 FAK 抑制剂的耐药性。

IF 11.1 1区医学

EMBO Molecular Medicine Pub Date : 2024-09-13 DOI: 10.1038/s44321-024-00138-7

Chiara Pozzato,Gonçalo Outeiro-Pinho,Mirco Galiè,Giorgio Ramadori,Georgia Konstantinidou

{"title":"ERK5 suppression overcomes FAK inhibitor resistance in mutant KRAS-driven non-small cell lung cancer.","authors":"Chiara Pozzato,Gonçalo Outeiro-Pinho,Mirco Galiè,Giorgio Ramadori,Georgia Konstantinidou","doi":"10.1038/s44321-024-00138-7","DOIUrl":"https://doi.org/10.1038/s44321-024-00138-7","url":null,"abstract":"Mutated KRAS serves as the oncogenic driver in 30% of non-small cell lung cancers (NSCLCs) and is associated with metastatic and therapy-resistant tumors. Focal Adhesion Kinase (FAK) acts as a mediator in sustaining KRAS-driven lung tumors, and although FAK inhibitors are currently undergoing clinical development, clinical data indicated that their efficacy in producing long-term anti-tumor responses is limited. Here we revealed two FAK interactors, extracellular-signal-regulated kinase 5 (ERK5) and cyclin-dependent kinase 5 (CDK5), as key players underlying FAK-mediated maintenance of KRAS mutant NSCLC. Inhibition of ERK5 and CDK5 synergistically suppressed FAK function, decreased proliferation and induced apoptosis owing to exacerbated ROS-induced DNA damage. Accordingly, concomitant pharmacological inhibition of ERK5 and CDK5 in a mouse model of KrasG12D-driven lung adenocarcinoma suppressed tumor progression and promoted cancer cell death. Cancer cells resistant to FAK inhibitors showed enhanced ERK5-FAK signaling dampening DNA damage. Notably, ERK5 inhibition prevented the development of resistance to FAK inhibitors, significantly enhancing the efficacy of anti-tumor responses. Therefore, we propose ERK5 inhibition as a potential co-targeting strategy to counteract FAK inhibitor resistance in NSCLC.","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":"11 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142233519","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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

An intrinsic mechanism of metabolic tuning promotes cardiac resilience to stress. 新陈代谢调整的内在机制促进了心脏对压力的恢复能力。

IF 11.1 1区医学

EMBO Molecular Medicine Pub Date : 2024-09-13 DOI: 10.1038/s44321-024-00132-z

Matteo Sorge,Giulia Savoré,Andrea Gallo,Davide Acquarone,Mauro Sbroggiò,Silvia Velasco,Federica Zamporlini,Saveria Femminò,Enrico Moiso,Giampaolo Morciano,Elisa Balmas,Andrea Raimondi,Gabrielle Nattenberg,Rachele Stefania,Carlo Tacchetti,Angela Maria Rizzo,Paola Corsetto,Alessandra Ghigo,Emilia Turco,Fiorella Altruda,Lorenzo Silengo,Paolo Pinton,Nadia Raffaelli,Nathan J Sniadecki,Claudia Penna,Pasquale Pagliaro,Emilio Hirsch,Chiara Riganti,Guido Tarone,Alessandro Bertero,Mara Brancaccio

{"title":"An intrinsic mechanism of metabolic tuning promotes cardiac resilience to stress.","authors":"Matteo Sorge,Giulia Savoré,Andrea Gallo,Davide Acquarone,Mauro Sbroggiò,Silvia Velasco,Federica Zamporlini,Saveria Femminò,Enrico Moiso,Giampaolo Morciano,Elisa Balmas,Andrea Raimondi,Gabrielle Nattenberg,Rachele Stefania,Carlo Tacchetti,Angela Maria Rizzo,Paola Corsetto,Alessandra Ghigo,Emilia Turco,Fiorella Altruda,Lorenzo Silengo,Paolo Pinton,Nadia Raffaelli,Nathan J Sniadecki,Claudia Penna,Pasquale Pagliaro,Emilio Hirsch,Chiara Riganti,Guido Tarone,Alessandro Bertero,Mara Brancaccio","doi":"10.1038/s44321-024-00132-z","DOIUrl":"https://doi.org/10.1038/s44321-024-00132-z","url":null,"abstract":"Defining the molecular mechanisms underlying cardiac resilience is crucial to find effective approaches to protect the heart. A physiologic level of ROS is produced in the heart by fatty acid oxidation, but stressful events can boost ROS and cause mitochondrial dysfunction and cardiac functional impairment. Melusin is a muscle specific chaperone required for myocardial compensatory remodeling during stress. Here we report that Melusin localizes in mitochondria where it binds the mitochondrial trifunctional protein, a key enzyme in fatty acid oxidation, and decreases it activity. Studying both mice and human induced pluripotent stem cell-derived cardiomyocytes, we found that Melusin reduces lipid oxidation in the myocardium and limits ROS generation in steady state and during pressure overload and doxorubicin treatment, preventing mitochondrial dysfunction. Accordingly, the treatment with the lipid oxidation inhibitor Trimetazidine concomitantly with stressful stimuli limits ROS accumulation and prevents long-term heart dysfunction. These findings disclose a physiologic mechanism of metabolic regulation in the heart and demonstrate that a timely restriction of lipid metabolism represents a potential therapeutic strategy to improve cardiac resilience to stress.","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":"34 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142233522","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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

CRISPR-enabled point-of-care genotyping for APOL1 genetic risk assessment. 用于 APOL1 遗传风险评估的 CRISPR 支持的护理点基因分型。

IF 11.1 1区医学

EMBO Molecular Medicine Pub Date : 2024-09-13 DOI: 10.1038/s44321-024-00126-x

Robert Greensmith,Isadora T Lape,Cristian V Riella,Alexander J Schubert,Jakob J Metzger,Anand S Dighe,Xiao Tan,Bernhard Hemmer,Josefine Rau,Sarah Wendlinger,Nora Diederich,Anja Schütz,Leonardo V Riella,Michael M Kaminski

{"title":"CRISPR-enabled point-of-care genotyping for APOL1 genetic risk assessment.","authors":"Robert Greensmith,Isadora T Lape,Cristian V Riella,Alexander J Schubert,Jakob J Metzger,Anand S Dighe,Xiao Tan,Bernhard Hemmer,Josefine Rau,Sarah Wendlinger,Nora Diederich,Anja Schütz,Leonardo V Riella,Michael M Kaminski","doi":"10.1038/s44321-024-00126-x","DOIUrl":"https://doi.org/10.1038/s44321-024-00126-x","url":null,"abstract":"Detecting genetic variants enables risk factor identification, disease screening, and initiation of preventative therapeutics. However, current methods, relying on hybridization or sequencing, are unsuitable for point-of-care settings. In contrast, CRISPR-based-diagnostics offer high sensitivity and specificity for point-of-care applications. While these methods have predominantly been used for pathogen sensing, their utilization for genotyping is limited. Here, we report a multiplexed CRISPR-based genotyping assay using LwaCas13a, PsmCas13b, and LbaCas12a, enabling the simultaneous detection of six genotypes. We applied this assay to identify genetic variants in the APOL1 gene prevalent among African Americans, which are associated with an 8-30-fold increase in the risk of developing kidney disease. Machine learning facilitated robust analysis across a multicenter clinical cohort of more than 100 patients, accurately identifying their genotypes. In addition, we optimized the readout using a multi-analyte lateral-flow assay demonstrating the ability for simplified genotype determination of clinical samples. Our CRISPR-based genotyping assay enables cost-effective point-of-care genetic variant detection due to its simplicity, versatility, and fast readout.","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":"12 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142233520","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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

A critical role for HNF4α in polymicrobial sepsis-associated metabolic reprogramming and death. HNF4α在多微生物败血症相关代谢重编程和死亡中的关键作用

IF 11.1 1区医学

EMBO Molecular Medicine Pub Date : 2024-09-11 DOI: 10.1038/s44321-024-00130-1

Céline Van Dender,Steven Timmermans,Ville Paakinaho,Tineke Vanderhaeghen,Jolien Vandewalle,Maarten Claes,Bruno Garcia,Bart Roman,Jan De Waele,Siska Croubels,Karolien De Bosscher,Philip Meuleman,Antoine Herpain,Jorma J Palvimo,Claude Libert

{"title":"A critical role for HNF4α in polymicrobial sepsis-associated metabolic reprogramming and death.","authors":"Céline Van Dender,Steven Timmermans,Ville Paakinaho,Tineke Vanderhaeghen,Jolien Vandewalle,Maarten Claes,Bruno Garcia,Bart Roman,Jan De Waele,Siska Croubels,Karolien De Bosscher,Philip Meuleman,Antoine Herpain,Jorma J Palvimo,Claude Libert","doi":"10.1038/s44321-024-00130-1","DOIUrl":"https://doi.org/10.1038/s44321-024-00130-1","url":null,"abstract":"In sepsis, limited food intake and increased energy expenditure induce a starvation response, which is compromised by a quick decline in the expression of hepatic PPARα, a transcription factor essential in intracellular catabolism of free fatty acids. The mechanism upstream of this PPARα downregulation is unknown. We found that sepsis causes a progressive hepatic loss-of-function of HNF4α, which has a strong impact on the expression of several important nuclear receptors, including PPARα. HNF4α depletion in hepatocytes dramatically increases sepsis lethality, steatosis, and organ damage and prevents an adequate response to IL6, which is critical for liver regeneration and survival. An HNF4α agonist protects against sepsis at all levels, irrespectively of bacterial loads, suggesting HNF4α is crucial in tolerance to sepsis. In conclusion, hepatic HNF4α activity is decreased during sepsis, causing PPARα downregulation, metabolic problems, and a disturbed IL6-mediated acute phase response. The findings provide new insights and therapeutic options in sepsis.","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":"10 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142174785","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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

Trained immunity of intestinal tuft cells during infancy enhances host defense against enteroviral infections in mice. 婴儿期肠簇细胞的免疫训练可增强小鼠宿主对肠道病毒感染的防御能力。

IF 11.1 1区医学

EMBO Molecular Medicine Pub Date : 2024-09-11 DOI: 10.1038/s44321-024-00128-9

Deyan Chen,Jing Wu,Fang Zhang,Ruining Lyu,Qiao You,Yajie Qian,Yurong Cai,Xiaoyan Tian,Hongji Tao,Yating He,Waqas Nawaz,Zhiwei Wu

{"title":"Trained immunity of intestinal tuft cells during infancy enhances host defense against enteroviral infections in mice.","authors":"Deyan Chen,Jing Wu,Fang Zhang,Ruining Lyu,Qiao You,Yajie Qian,Yurong Cai,Xiaoyan Tian,Hongji Tao,Yating He,Waqas Nawaz,Zhiwei Wu","doi":"10.1038/s44321-024-00128-9","DOIUrl":"https://doi.org/10.1038/s44321-024-00128-9","url":null,"abstract":"Innate immune cells have been acknowledged as trainable in recent years. While intestinal tuft cells are recognized for their crucial roles in the host defense against intestinal pathogens, there remains uncertainty regarding their trainability. Enterovirus 71 (EV71), a prevalent enterovirus that primarily infects children but rarely infects adults. At present, there is a significant expansion of intestinal tuft cells in the EV71-infected mouse model, which is associated with EV71-induced interleukin-25 (IL-25) production. Further, we found that IL-25 pre-treatment at 2 weeks old mouse enabled tuft cells to acquire immune memory. This was evidenced by the rapid expansion and stronger response of IL-25-trained tuft cells in response to EV71 infection at 6 weeks old, surpassing the reactivity of naïve tuft cells in mice without IL-25-trained progress. Interestingly, IL-25-trained intestinal tuft cells exhibit anti-enteroviral effect via producing a higher level of IL-25. Mechanically, IL-25 treatment upregulates spermidine/spermine acetyl-transferase enzyme (SAT1) expression, mediates intracellular polyamine deficiency, further inhibits enterovirus replication. In summary, tuft cells can be trained by IL-25, which supports faster and higher level IL-25 production in response to EV71 infection and further exhibits anti-enteroviral effect via SAT1-mediated intracellular polyamine deficiency. Given that IL-25 can be induced by multiple gut microbes during human growth and development, including shifts in gut flora abundance, which may partially explain the different susceptibility to enteroviral infections between adults and children.","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":"149 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142174643","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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

"Cruising together"-ASC specks and SAA, a perfect match in chronic inflammation. "同舟共济"--ASC斑点和SAA，慢性炎症的绝配。

IF 9 1区医学

EMBO Molecular Medicine Pub Date : 2024-09-01 Epub Date: 2024-07-30 DOI: 10.1038/s44321-024-00109-y

Salie Maasewerd, Bernardo Simoes Franklin

引用次数: 0

The RhoB p.S73F mutation leads to cerebral palsy through dysregulation of lipid homeostasis. RhoB p.S73F突变通过脂质平衡失调导致脑瘫。

IF 9 1区医学

EMBO Molecular Medicine Pub Date : 2024-09-01 Epub Date: 2024-07-30 DOI: 10.1038/s44321-024-00113-2

Xinyu Wu, Ruonan Liu, Zhongtian Zhang, Jie Yang, Xin Liu, Liqiang Jiang, Mengmeng Fang, Shoutang Wang, Liangxue Lai, Yuning Song, Zhanjun Li

{"title":"The RhoB p.S73F mutation leads to cerebral palsy through dysregulation of lipid homeostasis.","authors":"Xinyu Wu, Ruonan Liu, Zhongtian Zhang, Jie Yang, Xin Liu, Liqiang Jiang, Mengmeng Fang, Shoutang Wang, Liangxue Lai, Yuning Song, Zhanjun Li","doi":"10.1038/s44321-024-00113-2","DOIUrl":"10.1038/s44321-024-00113-2","url":null,"abstract":"Cerebral palsy (CP) is a prevalent neurological disorder that imposes a significant burden on children, families, and society worldwide. Recently, the RhoB p.S73F mutation was identified as a de novo mutation associated with CP. However, the mechanism by which the RhoB p.S73F mutation causes CP is currently unclear. In this study, rabbit models were generated to mimic the human RhoB p.S73F mutation using the SpG-BE4max system, and exhibited the typical symptoms of human CP, such as periventricular leukomalacia and spastic-dystonic diplegia. Further investigation revealed that the RhoB p.S73F mutation could activate ACAT1 through the LYN pathway, and the subsequently altered lipid levels may lead to neuronal and white matter damage resulting in the development of CP. This study presented the first mammalian model of genetic CP that accurately replicates the RhoB p.S73F mutation in humans, provided further insights between RhoB and lipid metabolism, and novel therapeutic targets for human CP.","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":"2002-2023"},"PeriodicalIF":9.0,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11393352/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141855153","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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

Histidine-rich glycoprotein modulates neutrophils and thrombolysis-associated hemorrhagic transformation. 富含组氨酸糖蛋白可调节中性粒细胞和溶栓相关出血转化。

IF 9 1区医学

EMBO Molecular Medicine Pub Date : 2024-09-01 Epub Date: 2024-08-15 DOI: 10.1038/s44321-024-00117-y

Wei Jiang, Yuexin Zhao, Rongrong Liu, Bohao Zhang, Yuhan Xie, Bin Gao, Kaibin Shi, Ming Zou, Dongmei Jia, Jiayue Ding, Xiaowei Hu, Yanli Duan, Ranran Han, DeRen Huang, Luc Van Kaer, Fu-Dong Shi

{"title":"Histidine-rich glycoprotein modulates neutrophils and thrombolysis-associated hemorrhagic transformation.","authors":"Wei Jiang, Yuexin Zhao, Rongrong Liu, Bohao Zhang, Yuhan Xie, Bin Gao, Kaibin Shi, Ming Zou, Dongmei Jia, Jiayue Ding, Xiaowei Hu, Yanli Duan, Ranran Han, DeRen Huang, Luc Van Kaer, Fu-Dong Shi","doi":"10.1038/s44321-024-00117-y","DOIUrl":"10.1038/s44321-024-00117-y","url":null,"abstract":"Intravenous thrombolysis using recombinant tissue plasminogen activator (tPA) remains the primary treatment for patients with acute ischemic stroke (AIS). However, the mechanism of tPA-related hemorrhagic transformation (HT) remains poorly understood. Elevation of histidine-rich glycoprotein (HRG) expression was detected by nano-liquid chromatography tandem mass spectrometry at 1 h following tPA infusion as compared to baseline prior to tPA infusion (discovery cohort, n = 10), which was subsequently confirmed in a validation cohort (n = 157) by ELISA. Surprisingly, no elevation of HRG was detected in individuals who subsequently developed HT. During in vitro experiments, HRG reduced neutrophil NETosis, inflammatory cytokine production, and migration across the blood-brain barrier induced by tPA. In a photothrombotic murine AIS model, HRG administration ameliorated HT with delayed thrombolysis, by inhibiting neutrophil immune infiltration and downregulating pro-inflammatory signaling pathways. Neutrophil depletion or NETosis inhibition also alleviated HT, whereas HRG siRNA treatment exacerbated HT. In conclusion, fluctuations in HRG levels may reflect tPA therapy and its associated HT. The inhibitory effect of HRG on neutrophils may counteract tPA-induced immune abnormalities and HT in patients with AIS.","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":"2146-2169"},"PeriodicalIF":9.0,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11393346/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141987659","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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

Therapeutic targeting ERRγ suppresses metastasis via extracellular matrix remodeling in small cell lung cancer. 针对ERRγ的治疗可通过细胞外基质重塑抑制小细胞肺癌的转移。

IF 9 1区医学

EMBO Molecular Medicine Pub Date : 2024-09-01 Epub Date: 2024-07-31 DOI: 10.1038/s44321-024-00108-z

Hong Wang, Huizi Sun, Jie Huang, Zhenhua Zhang, Guodi Cai, Chaofan Wang, Kai Xiao, Xiaofeng Xiong, Jian Zhang, Peiqing Liu, Xiaoyun Lu, Weineng Feng, Junjian Wang

{"title":"Therapeutic targeting ERRγ suppresses metastasis via extracellular matrix remodeling in small cell lung cancer.","authors":"Hong Wang, Huizi Sun, Jie Huang, Zhenhua Zhang, Guodi Cai, Chaofan Wang, Kai Xiao, Xiaofeng Xiong, Jian Zhang, Peiqing Liu, Xiaoyun Lu, Weineng Feng, Junjian Wang","doi":"10.1038/s44321-024-00108-z","DOIUrl":"10.1038/s44321-024-00108-z","url":null,"abstract":"Small-cell lung cancer (SCLC) is the most aggressive and lethal type of lung cancer, characterized by limited treatment options, early and frequent metastasis. However, the determinants of metastasis in SCLC are poorly defined. Here, we show that estrogen-related receptor gamma (ERRγ) is overexpressed in metastatic SCLC tumors, and is positively associated with SCLC progression. ERRγ functions as an essential activator of extracellular matrix (ECM) remodeling and cell adhesion, two critical steps in metastasis, by directly regulating the expression of major genes involved in these processes. Genetic and pharmacological inhibition of ERRγ markedly reduces collagen production, cell-matrix adhesion, microfilament production, and eventually blocks SCLC cell invasion and tumor metastasis. Notably, ERRγ antagonists significantly suppressed tumor growth and metastasis and restored SCLC vulnerability to chemotherapy in multiple cell-derived and patient-derived xenograft models. Taken together, these findings establish ERRγ as an attractive target for metastatic SCLC and provide a potential pharmacological strategy for treating this lethal disease.","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":"2043-2059"},"PeriodicalIF":9.0,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11393344/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141859283","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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

Inhibition of GSK3α,β rescues cognitive phenotypes in a preclinical mouse model of CTNNB1 syndrome. 抑制 GSK3α、β 可挽救 CTNNB1 综合征临床前小鼠模型的认知表型。

IF 9 1区医学

EMBO Molecular Medicine Pub Date : 2024-09-01 Epub Date: 2024-08-05 DOI: 10.1038/s44321-024-00110-5

Jonathan M Alexander, Leeanne Vazquez-Ramirez, Crystal Lin, Pantelis Antonoudiou, Jamie Maguire, Florence Wagner, Michele H Jacob

{"title":"Inhibition of GSK3α,β rescues cognitive phenotypes in a preclinical mouse model of CTNNB1 syndrome.","authors":"Jonathan M Alexander, Leeanne Vazquez-Ramirez, Crystal Lin, Pantelis Antonoudiou, Jamie Maguire, Florence Wagner, Michele H Jacob","doi":"10.1038/s44321-024-00110-5","DOIUrl":"10.1038/s44321-024-00110-5","url":null,"abstract":"CTNNB1 syndrome is a rare monogenetic disorder caused by CTNNB1 de novo pathogenic heterozygous loss-of-function variants that result in cognitive and motor disabilities. Treatment is currently lacking; our study addresses this critical need. CTNNB1 encodes β-catenin which is essential for normal brain function via its dual roles in cadherin-based synaptic adhesion complexes and canonical Wnt signal transduction. We have generated a Ctnnb1 germline heterozygous mouse line that displays cognitive and motor deficits, resembling key features of CTNNB1 syndrome in humans. Compared with wild-type littermates, Ctnnb1 heterozygous mice also exhibit decreases in brain β-catenin, β-catenin association with N-cadherin, Wnt target gene expression, and Na/K ATPases, key regulators of changes in ion gradients during high activity. Consistently, hippocampal neuron functional properties and excitability are altered. Most important, we identify a highly selective inhibitor of glycogen synthase kinase (GSK)3α,β that significantly normalizes the phenotypes to closely meet wild-type littermate levels. Our data provide new insights into brain molecular and functional changes, and the first evidence for an efficacious treatment with therapeutic potential for individuals with CTNNB1 syndrome.","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":"2109-2131"},"PeriodicalIF":9.0,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11393422/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141893177","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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