EMBO Molecular MedicinePub Date : 2024-11-01Epub Date: 2024-10-11DOI: 10.1038/s44321-024-00146-7
Yi Guo, Chuanbin Cai, Bingjie Zhang, Bo Tan, Qinmin Tang, Zhifeng Lei, Xiaolan Qi, Jiang Chen, Xiaojiang Zheng, Dan Zi, Song Li, Jun Tan
{"title":"Targeting USP11 regulation by a novel lithium-organic coordination compound improves neuropathologies and cognitive functions in Alzheimer transgenic mice.","authors":"Yi Guo, Chuanbin Cai, Bingjie Zhang, Bo Tan, Qinmin Tang, Zhifeng Lei, Xiaolan Qi, Jiang Chen, Xiaojiang Zheng, Dan Zi, Song Li, Jun Tan","doi":"10.1038/s44321-024-00146-7","DOIUrl":"10.1038/s44321-024-00146-7","url":null,"abstract":"<p><p>Alzheimer's Disease (AD), as the most common neurodegenerative disease worldwide, severely impairs patients' cognitive functions. Although its exact etiology remains unclear, the abnormal aggregations of misfolded β-amyloid peptide and tau protein are considered pivotal in its pathological progression. Recent studies identify ubiquitin-specific protease 11 (USP11) as the key regulator of tau deubiquitination, exacerbating tau aggregation and AD pathology. Thereby, inhibiting USP11 function, via either blocking USP11 activity or lowering USP11 protein level, may serve as an effective therapeutic strategy against AD. Our research introduces IsoLiPro, a unique lithium isobutyrate-L-proline coordination compound, effectively lowers USP11 protein level and enhances tau ubiquitination in vitro. Additionally, long-term oral administration of IsoLiPro dramatically reduces total and phosphorylated tau levels in AD transgenic mice. Moreover, IsoLiPro also significantly lessens β-amyloid deposition and synaptic damage, improving cognitive functions in these animal models. These results indicate that IsoLiPro, as a novel small-molecule USP11 inhibitor, can effectively alleviate AD-like pathologies and improve cognitive functions, offering promise as a potential multi-targeting therapeutic agent against AD.</p>","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":"2856-2881"},"PeriodicalIF":9.0,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11555261/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142406240","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}
EMBO Molecular MedicinePub Date : 2024-11-01Epub Date: 2024-10-15DOI: 10.1038/s44321-024-00153-8
Nastaran Khazamipour, Htoo Zarni Oo, Nader Al-Nakouzi, Mona Marzban, Nasrin Khazamipour, Morgan E Roberts, Negin Farivar, Igor Moskalev, Joey Lo, Fariba Ghaidi, Irina Nelepcu, Alireza Moeen, Sarah Truong, Robert Dagil, Swati Choudhary, Tobias Gustavsson, Beibei Zhai, Sabine Heitzender, Ali Salanti, Poul H Sorensen, Mads Daugaard
{"title":"Transient CAR T cells with specificity to oncofetal glycosaminoglycans in solid tumors.","authors":"Nastaran Khazamipour, Htoo Zarni Oo, Nader Al-Nakouzi, Mona Marzban, Nasrin Khazamipour, Morgan E Roberts, Negin Farivar, Igor Moskalev, Joey Lo, Fariba Ghaidi, Irina Nelepcu, Alireza Moeen, Sarah Truong, Robert Dagil, Swati Choudhary, Tobias Gustavsson, Beibei Zhai, Sabine Heitzender, Ali Salanti, Poul H Sorensen, Mads Daugaard","doi":"10.1038/s44321-024-00153-8","DOIUrl":"10.1038/s44321-024-00153-8","url":null,"abstract":"<p><p>Glycosaminoglycans are often deprioritized as targets for synthetic immunotherapy due to the complexity of glyco-epitopes and limited options for obtaining specific subtype binding. Solid tumors express proteoglycans that are modified with oncofetal chondroitin sulfate (CS), a modification normally restricted to the placenta. Here, we report the design and functionality of transient chimeric antigen receptor (CAR) T cells with selectivity to oncofetal CS. Following expression in T cells, the CAR could be \"armed\" with recombinant VAR2CSA lectins (rVAR2) to target tumor cells expressing oncofetal CS. While unarmed CAR T cells remained inactive in the presence of target cells, VAR2-armed CAR T cells displayed robust activation and the ability to eliminate diverse tumor cell types in vitro. Cytotoxicity of the CAR T cells was proportional to the concentration of rVAR2 available to the CAR, offering a potential molecular handle to finetune CAR T cell activity. In vivo, armed CAR T cells rapidly targeted bladder tumors and increased the survival of tumor-bearing mice. Thus, our work indicates that cancer-restricted glycosaminoglycans may be exploited as potential targets for CAR T cell therapy.</p>","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":"2775-2794"},"PeriodicalIF":9.0,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11554890/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142460740","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}
EMBO Molecular MedicinePub Date : 2024-11-01Epub Date: 2024-10-28DOI: 10.1038/s44321-024-00149-4
Elisa Cappio Barazzone, Médéric Diard, Isabelle Hug, Louise Larsson, Emma Slack
{"title":"Diagnosing and engineering gut microbiomes.","authors":"Elisa Cappio Barazzone, Médéric Diard, Isabelle Hug, Louise Larsson, Emma Slack","doi":"10.1038/s44321-024-00149-4","DOIUrl":"10.1038/s44321-024-00149-4","url":null,"abstract":"<p><p>The microbes, nutrients and toxins that we are exposed to can have a profound effect on the composition and function of the gut microbiome. Thousands of peer-reviewed publications link microbiome composition and function to health from the moment of birth, right through to centenarians, generating a tantalizing glimpse of what might be possible if we could intervene rationally. Nevertheless, there remain relatively few real-world examples where successful microbiome engineering leads to beneficial health effects. Here we aim to provide a framework for the progress needed to turn gut microbiome engineering from a trial-and-error approach to a rational medical intervention. The workflow starts with truly understanding and accurately diagnosing the problems that we are trying to fix, before moving on to developing technologies that can achieve the desired changes.</p>","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":"2660-2677"},"PeriodicalIF":9.0,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11554810/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142521392","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}
EMBO Molecular MedicinePub Date : 2024-11-01Epub Date: 2024-10-02DOI: 10.1038/s44321-024-00143-w
Aude Boulay, Emmanuel Quevarec, Isabelle Malet, Giuseppe Nicastro, Célia Chamontin, Suzon Perrin, Corinne Henriquet, Martine Pugnière, Valérie Courgnaud, Mickaël Blaise, Anne-Geneviève Marcelin, Ian A Taylor, Laurent Chaloin, Nathalie J Arhel
{"title":"A new class of capsid-targeting inhibitors that specifically block HIV-1 nuclear import.","authors":"Aude Boulay, Emmanuel Quevarec, Isabelle Malet, Giuseppe Nicastro, Célia Chamontin, Suzon Perrin, Corinne Henriquet, Martine Pugnière, Valérie Courgnaud, Mickaël Blaise, Anne-Geneviève Marcelin, Ian A Taylor, Laurent Chaloin, Nathalie J Arhel","doi":"10.1038/s44321-024-00143-w","DOIUrl":"10.1038/s44321-024-00143-w","url":null,"abstract":"<p><p>HIV-1 capsids cross nuclear pore complexes (NPCs) by engaging with the nuclear import machinery. To identify compounds that inhibit HIV-1 nuclear import, we screened drugs in silico on a three-dimensional model of a CA hexamer bound by Transportin-1 (TRN-1). Among hits, compound H27 inhibited HIV-1 with a low micromolar IC<sub>50</sub>. Unlike other CA-targeting compounds, H27 did not alter CA assembly or disassembly, inhibited nuclear import specifically, and retained antiviral activity against PF74- and Lenacapavir-resistant mutants. The differential sensitivity of divergent primate lentiviral capsids, capsid stability and H27 escape mutants, together with structural analyses, suggest that H27 makes multiple low affinity contacts with assembled capsid. Interaction experiments indicate that H27 may act by preventing CA from engaging with components of the NPC machinery such as TRN-1. H27 exhibited good metabolic stability in vivo and was efficient against different subtypes and circulating recombinant forms from treatment-naïve patients as well as strains resistant to the four main classes of antiretroviral drugs. This work identifies compounds that demonstrate a novel mechanism of action by specifically blocking HIV-1 nuclear import.</p>","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":"2918-2945"},"PeriodicalIF":9.0,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11555092/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142364848","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}
EMBO Molecular MedicinePub Date : 2024-11-01Epub Date: 2024-10-02DOI: 10.1038/s44321-024-00145-8
Jan Mašek, Iva Filipovic, Noémi Van Hul, Lenka Belicová, Markéta Jiroušková, Daniel V Oliveira, Anna Maria Frontino, Simona Hankeova, Jingyan He, Fabio Turetti, Afshan Iqbal, Igor Červenka, Lenka Sarnová, Elisabeth Verboven, Tomáš Brabec, Niklas K Björkström, Martin Gregor, Jan Dobeš, Emma R Andersson
{"title":"Jag1 insufficiency alters liver fibrosis via T cell and hepatocyte differentiation defects.","authors":"Jan Mašek, Iva Filipovic, Noémi Van Hul, Lenka Belicová, Markéta Jiroušková, Daniel V Oliveira, Anna Maria Frontino, Simona Hankeova, Jingyan He, Fabio Turetti, Afshan Iqbal, Igor Červenka, Lenka Sarnová, Elisabeth Verboven, Tomáš Brabec, Niklas K Björkström, Martin Gregor, Jan Dobeš, Emma R Andersson","doi":"10.1038/s44321-024-00145-8","DOIUrl":"10.1038/s44321-024-00145-8","url":null,"abstract":"<p><p>Fibrosis contributes to tissue repair, but excessive fibrosis disrupts organ function. Alagille syndrome (ALGS, caused by mutations in JAGGED1) results in liver disease and characteristic fibrosis. Here, we show that Jag1<sup>Ndr/Ndr</sup> mice, a model for ALGS, recapitulate ALGS-like fibrosis. Single-cell RNA-seq and multi-color flow cytometry of the liver revealed immature hepatocytes and paradoxically low intrahepatic T cell infiltration despite cholestasis in Jag1<sup>Ndr/Ndr</sup> mice. Thymic and splenic regulatory T cells (Tregs) were enriched and Jag1<sup>Ndr/Ndr</sup> lymphocyte immune and fibrotic capacity was tested with adoptive transfer into Rag1<sup>-/-</sup> mice, challenged with dextran sulfate sodium (DSS) or bile duct ligation (BDL). Transplanted Jag1<sup>Ndr/Ndr</sup> lymphocytes were less inflammatory with fewer activated T cells than Jag1<sup>+/+</sup> lymphocytes in response to DSS. Cholestasis induced by BDL in Rag1<sup>-/-</sup> mice with Jag1<sup>Ndr/Ndr</sup> lymphocytes resulted in periportal Treg accumulation and three-fold less periportal fibrosis than in Rag1<sup>-/-</sup> mice with Jag1<sup>+/+</sup> lymphocytes. Finally, the Jag1<sup>Ndr/Ndr</sup> hepatocyte expression profile and Treg overrepresentation were corroborated in patients' liver samples. Jag1-dependent hepatic and immune defects thus interact to determine the fibrotic process in ALGS.</p>","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":"2946-2975"},"PeriodicalIF":11.3,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11554675/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142364849","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}
EMBO Molecular MedicinePub Date : 2024-11-01Epub Date: 2024-10-21DOI: 10.1038/s44321-024-00142-x
Tobias Ackermann, Engy Shokry, Ruhi Deshmukh, Jayanthi Anand, Laura C A Galbraith, Louise Mitchell, Giovanny Rodriguez-Blanco, Victor H Villar, Britt Amber Sterken, Colin Nixon, Sara Zanivan, Karen Blyth, David Sumpton, Saverio Tardito
{"title":"Breast cancer secretes anti-ferroptotic MUFAs and depends on selenoprotein synthesis for metastasis.","authors":"Tobias Ackermann, Engy Shokry, Ruhi Deshmukh, Jayanthi Anand, Laura C A Galbraith, Louise Mitchell, Giovanny Rodriguez-Blanco, Victor H Villar, Britt Amber Sterken, Colin Nixon, Sara Zanivan, Karen Blyth, David Sumpton, Saverio Tardito","doi":"10.1038/s44321-024-00142-x","DOIUrl":"10.1038/s44321-024-00142-x","url":null,"abstract":"<p><p>The limited availability of therapeutic options for patients with triple-negative breast cancer (TNBC) contributes to the high rate of metastatic recurrence and poor prognosis. Ferroptosis is a type of cell death caused by iron-dependent lipid peroxidation and counteracted by the antioxidant activity of the selenoprotein GPX4. Here, we show that TNBC cells secrete an anti-ferroptotic factor in the extracellular environment when cultured at high cell densities but are primed to ferroptosis when forming colonies at low density. We found that secretion of the anti-ferroptotic factors, identified as monounsaturated fatty acid (MUFA) containing lipids, and the vulnerability to ferroptosis of single cells depends on the low expression of stearyl-CoA desaturase (SCD) that is proportional to cell density. Finally, we show that the inhibition of Sec-tRNAsec biosynthesis, an essential step for selenoprotein production, causes ferroptosis and impairs the lung seeding of circulating TNBC cells that are no longer protected by the MUFA-rich environment of the primary tumour.</p>","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":"2749-2774"},"PeriodicalIF":9.0,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11555046/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142460739","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}
{"title":"Ependymal cell lineage reprogramming as a potential therapeutic intervention for hydrocephalus.","authors":"Konstantina Kaplani, Maria-Eleni Lalioti, Styliani Vassalou, Georgia Lokka, Evangelia Parlapani, Georgios Kritikos, Zoi Lygerou, Stavros Taraviras","doi":"10.1038/s44321-024-00156-5","DOIUrl":"10.1038/s44321-024-00156-5","url":null,"abstract":"<p><p>Hydrocephalus is a common neurological condition, characterized by the excessive accumulation of cerebrospinal fluid in the cerebral ventricles. Primary treatments for hydrocephalus mainly involve neurosurgical cerebrospinal fluid diversion, which hold high morbidity and failure rates, highlighting the necessity for the discovery of novel therapeutic approaches. Although the pathophysiology of hydrocephalus is highly multifactorial, impaired function of the brain ependymal cells plays a fundamental role in hydrocephalus. Here we show that GemC1 and McIdas, key regulators of multiciliated ependymal cell fate determination, induce direct cellular reprogramming towards ependyma. Our study reveals that ectopic expression of GemC1 and McIdas reprograms cortical astrocytes and programs mouse embryonic stem cells into ependyma. McIdas is sufficient to establish functional activity in the reprogrammed astrocytes. Furthermore, we show that McIdas' expression promotes ependymal cell regeneration in two different postnatal hydrocephalus mouse models: an intracranial hemorrhage and a genetic form of hydrocephalus and ameliorates the cytoarchitecture of the neurogenic niche. Our study provides evidence on the restoration of ependyma in animal models mimicking hydrocephalus that could be exploited towards future therapeutic interventions.</p>","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":"2725-2748"},"PeriodicalIF":9.0,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11555118/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142521393","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}
{"title":"Luteolin detoxifies DEHP and prevents liver injury by degrading Uroc1 protein in mice.","authors":"Huiting Wang, Ziting Zhao, Mingming Song, Wenxiang Zhang, Chang Liu, Siyu Chen","doi":"10.1038/s44321-024-00160-9","DOIUrl":"10.1038/s44321-024-00160-9","url":null,"abstract":"<p><p>Di-(2-ethylhexyl) phthalate (DEHP), an environmental pollutant, has been widely detected in both environmental and clinical samples, representing a serious threat to the homeostasis of the endocrine system. The accumulation of DEHP is notably pronounced in the liver and can lead to liver damage. The lack of effective high-throughput screening system retards the discovery of such drugs that can specifically target and eliminate the detrimental impact of DEHP. Here, by developing a Cy5-modified single-strand DNA-aptamer-based approach targeting DEHP, we have identified luteolin as a potential drug, which showcasing robust efficacy in detoxifying the DEHP by facilitating the expulsion of DEHP in both mouse primary hepatocytes and livers. Mechanistically, luteolin enhances the protein degradation of hepatic urocanate hydratase 1 (Uroc1) by targeting its Ala270 and Val272 sites. More importantly, trans-urocanic acid (trans-UCA), as the substrate of Uroc1, possesses properties similar to luteolin by regulating the lysosomal exocytosis through the inhibition of the ERK1/2 signal cascade. In summary, luteolin serves as a potent therapeutic agent in efficiently detoxifying DEHP in the liver by regulating the UCA/Uroc1 axis.</p>","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":"2699-2724"},"PeriodicalIF":9.0,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11555401/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142544430","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}
Van-Cuong Pham,Claudia Jasmin Rödel,Mariaelena Valentino,Matteo Malinverno,Alessio Paolini,Juliane Münch,Candice Pasquier,Favour C Onyeogaziri,Bojana Lazovic,Romuald Girard,Janne Koskimäki,Melina Hußmann,Benjamin Keith,Daniel Jachimowicz,Franziska Kohl,Astrid Hagelkruys,Josef M Penninger,Stefan Schulte-Merker,Issam A Awad,Ryan Hicks,Peetra U Magnusson,Eva Faurobert,Massimiliano Pagani,Salim Abdelilah-Seyfried
{"title":"Epigenetic regulation by polycomb repressive complex 1 promotes cerebral cavernous malformations.","authors":"Van-Cuong Pham,Claudia Jasmin Rödel,Mariaelena Valentino,Matteo Malinverno,Alessio Paolini,Juliane Münch,Candice Pasquier,Favour C Onyeogaziri,Bojana Lazovic,Romuald Girard,Janne Koskimäki,Melina Hußmann,Benjamin Keith,Daniel Jachimowicz,Franziska Kohl,Astrid Hagelkruys,Josef M Penninger,Stefan Schulte-Merker,Issam A Awad,Ryan Hicks,Peetra U Magnusson,Eva Faurobert,Massimiliano Pagani,Salim Abdelilah-Seyfried","doi":"10.1038/s44321-024-00152-9","DOIUrl":"https://doi.org/10.1038/s44321-024-00152-9","url":null,"abstract":"Cerebral cavernous malformations (CCMs) are anomalies of the cerebral vasculature. Loss of the CCM proteins CCM1/KRIT1, CCM2, or CCM3/PDCD10 trigger a MAPK-Krüppel-like factor 2 (KLF2) signaling cascade, which induces a pathophysiological pattern of gene expression. The downstream target genes that are activated by KLF2 are mostly unknown. Here we show that Chromobox Protein Homolog 7 (CBX7), component of the Polycomb Repressive Complex 1, contributes to pathophysiological KLF2 signaling during zebrafish cardiovascular development. CBX7/cbx7a mRNA is strongly upregulated in lesions of CCM patients, and in human, mouse, and zebrafish CCM-deficient endothelial cells. The silencing or pharmacological inhibition of CBX7/Cbx7a suppresses pathological CCM phenotypes in ccm2 zebrafish, CCM2-deficient HUVECs, and in a pre-clinical murine CCM3 disease model. Whole-transcriptome datasets from zebrafish cardiovascular tissues and human endothelial cells reveal a role of CBX7/Cbx7a in the activation of KLF2 target genes including TEK, ANGPT1, WNT9, and endoMT-associated genes. Our findings uncover an intricate interplay in the regulation of Klf2-dependent biomechanical signaling by CBX7 in CCM. This work also provides insights for therapeutic strategies in the pathogenesis of CCM.","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":"40 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2024-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142439505","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}
{"title":"Unraveling autophagic imbalances and therapeutic insights in Mecp2-deficient models.","authors":"Alessandro Esposito,Tommaso Seri,Martina Breccia,Marzia Indrigo,Giuseppina De Rocco,Francesca Nuzzolillo,Vanna Denti,Francesca Pappacena,Gaia Tartaglione,Simone Serrao,Giuseppe Paglia,Luca Murru,Stefano de Pretis,Jean-Michel Cioni,Nicoletta Landsberger,Fabrizia Claudia Guarnieri,Michela Palmieri","doi":"10.1038/s44321-024-00151-w","DOIUrl":"https://doi.org/10.1038/s44321-024-00151-w","url":null,"abstract":"Loss-of-function mutations in MECP2 are associated to Rett syndrome (RTT), a severe neurodevelopmental disease. Mainly working as a transcriptional regulator, MeCP2 absence leads to gene expression perturbations resulting in deficits of synaptic function and neuronal activity. In addition, RTT patients and mouse models suffer from a complex metabolic syndrome, suggesting that related cellular pathways might contribute to neuropathogenesis. Along this line, autophagy is critical in sustaining developing neuron homeostasis by breaking down dysfunctional proteins, lipids, and organelles.Here, we investigated the autophagic pathway in RTT and found reduced content of autophagic vacuoles in Mecp2 knock-out neurons. This correlates with defective lipidation of LC3B, probably caused by a deficiency of the autophagic membrane lipid phosphatidylethanolamine. The administration of the autophagy inducer trehalose recovers LC3B lipidation, autophagosomes content in knock-out neurons, and ameliorates their morphology, neuronal activity and synaptic ultrastructure. Moreover, we provide evidence for attenuation of motor and exploratory impairment in Mecp2 knock-out mice upon trehalose administration. Overall, our findings open new perspectives for neurodevelopmental disorders therapies based on the concept of autophagy modulation.","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":"13 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2024-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142439506","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}
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