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Cell Reports Jul 2023The adhesion G-protein-coupled receptor GPR133 (ADGRD1) supports growth of the brain malignancy glioblastoma. How the extracellular interactome of GPR133 in glioblastoma...
The adhesion G-protein-coupled receptor GPR133 (ADGRD1) supports growth of the brain malignancy glioblastoma. How the extracellular interactome of GPR133 in glioblastoma modulates signaling remains unknown. Here, we use affinity proteomics to identify the transmembrane protein PTK7 as an extracellular binding partner of GPR133 in glioblastoma. PTK7 binds the autoproteolytically generated N-terminal fragment of GPR133 and its expression in trans increases GPR133 signaling. This effect requires the intramolecular cleavage of GPR133 and PTK7's anchoring in the plasma membrane. PTK7's allosteric action on GPR133 signaling is additive with but topographically distinct from orthosteric activation by soluble peptide mimicking the endogenous tethered Stachel agonist. GPR133 and PTK7 are expressed in adjacent cells in glioblastoma, where their knockdown phenocopies each other. We propose that this ligand-receptor interaction is relevant to the pathogenesis of glioblastoma and possibly other physiological processes in healthy tissues.
Topics: Humans; Glioblastoma; Signal Transduction; Receptors, G-Protein-Coupled; Cell Membrane; Allosteric Regulation; Ligands; Allosteric Site; Cell Adhesion Molecules; Receptor Protein-Tyrosine Kinases
PubMed: 37354459
DOI: 10.1016/j.celrep.2023.112679 -
Genome Medicine Jul 2023Postmortem studies in schizophrenia consistently show reduced dendritic spines in the cerebral cortex but the mechanistic underpinnings of these deficits remain unknown....
BACKGROUND
Postmortem studies in schizophrenia consistently show reduced dendritic spines in the cerebral cortex but the mechanistic underpinnings of these deficits remain unknown. Recent genome-wide association studies and exome sequencing investigations implicate synaptic genes and processes in the disease biology of schizophrenia.
METHODS
We generated human cortical pyramidal neurons by differentiating iPSCs of seven schizophrenia patients and seven healthy subjects, quantified dendritic spines and synapses in different cortical neuron subtypes, and carried out transcriptomic studies to identify differentially regulated genes and aberrant cellular processes in schizophrenia.
RESULTS
Cortical neurons expressing layer III marker CUX1, but not those expressing layer V marker CTIP2, showed significant reduction in dendritic spine density in schizophrenia, mirroring findings in postmortem studies. Transcriptomic experiments in iPSC-derived cortical neurons showed that differentially expressed genes in schizophrenia were enriched for genes implicated in schizophrenia in genome-wide association and exome sequencing studies. Moreover, most of the differentially expressed genes implicated in schizophrenia genetic studies had lower expression levels in schizophrenia cortical neurons. Network analysis of differentially expressed genes led to identification of NRXN3 as a hub gene, and follow-up experiments showed specific reduction of the NRXN3 204 isoform in schizophrenia neurons. Furthermore, overexpression of the NRXN3 204 isoform in schizophrenia neurons rescued the spine and synapse deficits in the cortical neurons while knockdown of NRXN3 204 in healthy neurons phenocopied spine and synapse deficits seen in schizophrenia cortical neurons. The antipsychotic clozapine increased expression of the NRXN3 204 isoform in schizophrenia cortical neurons and rescued the spine and synapse density deficits.
CONCLUSIONS
Taken together, our findings in iPSC-derived cortical neurons recapitulate cell type-specific findings in postmortem studies in schizophrenia and have led to the identification of a specific isoform of NRXN3 that modulates synaptic deficits in schizophrenia neurons.
Topics: Humans; Schizophrenia; Transcriptome; Genome-Wide Association Study; Cerebral Cortex; Neurons; Stem Cells; Protein Isoforms
PubMed: 37507766
DOI: 10.1186/s13073-023-01203-5 -
Herzschrittmachertherapie &... Dec 2023Electrocardiographic findings and arrhythmias are common in cardiomyopathies. Both may be an early indication of a specific diagnosis or may occur due to myocardial... (Review)
Review
Electrocardiographic findings and arrhythmias are common in cardiomyopathies. Both may be an early indication of a specific diagnosis or may occur due to myocardial fibrosis and/or reduced contractility. Brady- and tachyarrhythmias significantly contribute to increased morbidity and mortality in patients with cardiomyopathies. Antiarrhythmic therapy including risk stratification is often challenging and plays a major role for these patients. Thus, an "electrophysiological" perspective on guidelines on cardiomyopathies may be warranted. As the European Society of Cardiology (ESC) has recently published a new guideline for the management of cardiomyopathies, this overview aims to present key messages of these guidelines. Innovations include a new phenotype-based classification system with emphasis on a multimodal imaging approach for diagnosis and risk stratification. The guideline includes detailed chapters on dilated and hypertrophic cardiomyopathy and their phenocopies, arrhythmogenic right ventricular cardiomyopathy, and restrictive cardiomyopathy as well as syndromic and metabolic cardiomyopathies. Patient pathways guide clinicians from the initial presentation to diagnosis. The role of cardiovascular magnetic resonance imaging and genetic testing during diagnostic work-up is stressed. Concepts of rhythm and rate control for atrial fibrillation have led to new recommendations, and the role of defibrillator therapy in primary prevention is discussed in detail. Whilst providing general guidelines for management, the primary objective of the guideline is to ascertain the disease etiology and disease-specific, individualized management.
Topics: Humans; Death, Sudden, Cardiac; Cardiomyopathies; Heart; Cardiomyopathy, Hypertrophic; Arrhythmias, Cardiac; Cardiology
PubMed: 37973628
DOI: 10.1007/s00399-023-00975-y -
Nature Communications Dec 2023Cytoglobin is a heme protein with unresolved physiological function. Genetic deletion of zebrafish cytoglobin (cygb2) causes developmental defects in left-right cardiac...
Cytoglobin is a heme protein with unresolved physiological function. Genetic deletion of zebrafish cytoglobin (cygb2) causes developmental defects in left-right cardiac determination, which in humans is associated with defects in ciliary function and low airway epithelial nitric oxide production. Here we show that Cygb2 co-localizes with cilia and with the nitric oxide synthase Nos2b in the zebrafish Kupffer's vesicle, and that cilia structure and function are disrupted in cygb2 mutants. Abnormal ciliary function and organ laterality defects are phenocopied by depletion of nos2b and of gucy1a, the soluble guanylate cyclase homolog in fish. The defects are rescued by exposing cygb2 mutant embryos to a nitric oxide donor or a soluble guanylate cyclase stimulator, or with over-expression of nos2b. Cytoglobin knockout mice also show impaired airway epithelial cilia structure and reduced nitric oxide levels. Altogether, our data suggest that cytoglobin is a positive regulator of a signaling axis composed of nitric oxide synthase-soluble guanylate cyclase-cyclic GMP that is necessary for normal cilia motility and left-right patterning.
Topics: Animals; Humans; Mice; Zebrafish; Zebrafish Proteins; Cytoglobin; Body Patterning; Nitric Oxide; Soluble Guanylyl Cyclase; Cilia; Nitric Oxide Synthase
PubMed: 38097556
DOI: 10.1038/s41467-023-43544-0 -
Platelets Dec 2023The field of proteomics and its application to platelet biology, is rapidly and promisingly developing. Platelets (and megakaryocytes) are postulated as biosensors of... (Review)
Review
The field of proteomics and its application to platelet biology, is rapidly and promisingly developing. Platelets (and megakaryocytes) are postulated as biosensors of health and disease, and their proteome poses as a tool to identify the specific health-disease hallmarks. Furthermore, the clinical management of certain pathologies where platelets are active players demands the development of alternative treatments, such is the case in patients where the balance thrombosis-bleeding is compromised, and a proteomics approach might aid at the identification of novel targets. Hereby, the mouse and human platelet proteomes and secretomes from public databases are compared, which shows that human and mouse platelets share a highly conserved proteome, considering identified proteins, and most importantly, their relative abundance. These supports, also interspecies wise, the use of the proteomics tool in the field, substantiated by a growing number of clinically relevant studies in humans or preclinical models. While the study of platelets through proteomics seems accessible and direct (. noninvasive blood sampling, enucleated), there are some points of concern regarding the quality control of samples for such proteomics studies. Importantly, the quality of the generated data is improving over the years, which will allow cross-study comparisons. In parallel, the application of proteomics to the megakaryocyte compartment has a promising but long journey ahead. We foresee and encourage the application of platelet proteomics for diagnostic/prognostic purposes even beyond hematopoiesis and transfusion medicine, and as a tool that will procure the improvement of current therapies and the development of alternative treatment options.
Topics: Humans; Animals; Mice; Blood Platelets; Proteomics; Proteome; Megakaryocytes
PubMed: 37283127
DOI: 10.1080/09537104.2023.2220415 -
Advanced Science (Weinheim,... Mar 2024The extracellular matrix (ECM) undergoes substantial changes during prostate cancer (PCa) progression, thereby regulating PCa growth and invasion. Herein, a... (Meta-Analysis)
Meta-Analysis
The extracellular matrix (ECM) undergoes substantial changes during prostate cancer (PCa) progression, thereby regulating PCa growth and invasion. Herein, a meta-analysis of multiple PCa cohorts is performed which revealed that downregulation or genomic loss of ITGA1 and ITGA2 integrin genes is associated with tumor progression and worse prognosis. Genomic deletion of both ITGA1 and ITGA2 activated epithelial-to-mesenchymal transition (EMT) in benign prostate epithelial cells, thereby enhancing their invasive potential in vitro and converting them into tumorigenic cells in vivo. Mechanistically, EMT is induced by enhanced secretion and autocrine activation of TGFβ1 and nuclear targeting of YAP1. An unbiased genome-wide co-expression analysis of large PCa cohort datasets identified the transcription factor TEAD1 as a key regulator of ITGA1 and ITGA2 expression in PCa cells while TEAD1 loss phenocopied the dual loss of α1- and α2-integrins in vitro and in vivo. Remarkably, clinical data analysis revealed that TEAD1 downregulation or genomic loss is associated with aggressive PCa and together with low ITGA1 and ITGA2 expression synergistically impacted PCa prognosis and progression. This study thus demonstrated that loss of α1- and α2-integrins, either via deletion/inactivation of the ITGA1/ITGA2 locus or via loss of TEAD1, contributes to PCa progression by inducing TGFβ1-driven EMT.
Topics: Male; Humans; Prostate; Cell Line, Tumor; Prostatic Neoplasms; Signal Transduction; Integrin alpha2; TEA Domain Transcription Factors
PubMed: 38169150
DOI: 10.1002/advs.202305547 -
Annual Review of Biomedical Data Science Aug 2023SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) infection is silent or benign in most infected individuals, but causes hypoxemic COVID-19 pneumonia in about... (Review)
Review
SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) infection is silent or benign in most infected individuals, but causes hypoxemic COVID-19 pneumonia in about 10% of cases. We review studies of the human genetics of life-threatening COVID-19 pneumonia, focusing on both rare and common variants. Large-scale genome-wide association studies have identified more than 20 common loci robustly associated with COVID-19 pneumonia with modest effect sizes, some implicating genes expressed in the lungs or leukocytes. The most robust association, on chromosome 3, concerns a haplotype inherited from Neanderthals. Sequencing studies focusing on rare variants with a strong effect have been particularly successful, identifying inborn errors of type I interferon (IFN) immunity in 1-5% of unvaccinated patients with critical pneumonia, and their autoimmune phenocopy, autoantibodies against type I IFN, in another 15-20% of cases. Our growing understanding of the impact of human genetic variation on immunity to SARS-CoV-2 is enabling health systems to improve protection for individuals and populations.
Topics: Humans; COVID-19; SARS-CoV-2; Genome-Wide Association Study; Interferon Type I; Genomics
PubMed: 37196358
DOI: 10.1146/annurev-biodatasci-020222-021705 -
Life Science Alliance Jul 2023MYC is a pleiotropic transcription factor involved in cancer, cell proliferation, and metabolism. Its regulation and function in NK cells, which are innate cytotoxic...
MYC is a pleiotropic transcription factor involved in cancer, cell proliferation, and metabolism. Its regulation and function in NK cells, which are innate cytotoxic lymphocytes important to control viral infections and cancer, remain poorly defined. Here, we show that mice deficient for Myc in NK cells presented a severe reduction in these lymphocytes. Myc was required for NK cell development and expansion in response to the key cytokine IL-15, which induced Myc through transcriptional and posttranslational mechanisms. Mechanistically, Myc ablation in vivo largely impacted NK cells' ribosomagenesis, reducing their translation and expansion capacities. Similar results were obtained by inhibiting MYC in human NK cells. Impairing translation by pharmacological intervention phenocopied the consequences of deleting or blocking MYC in vitro. Notably, mice lacking Myc in NK cells exhibited defective anticancer immunity, which reflected their decreased numbers of mature NK cells exerting suboptimal cytotoxic functions. These results indicate that MYC is a central node in NK cells, connecting IL-15 to translational fitness, expansion, and anticancer immunity.
Topics: Animals; Humans; Mice; Cytokines; Gene Expression Regulation; Interleukin-15; Killer Cells, Natural; Signal Transduction
PubMed: 37105715
DOI: 10.26508/lsa.202302069 -
Brain : a Journal of Neurology Mar 2024Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are two incurable neurodegenerative diseases that exist on a clinical, genetic and pathological...
Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are two incurable neurodegenerative diseases that exist on a clinical, genetic and pathological spectrum. The VCP gene is highly relevant, being directly implicated in both FTD and ALS. Here, we investigate the effects of VCP mutations on the cellular homoeostasis of human induced pluripotent stem cell-derived cortical neurons, focusing on endolysosomal biology and tau pathology. We found that VCP mutations cause abnormal accumulation of enlarged endolysosomes accompanied by impaired interaction between two nuclear RNA binding proteins: fused in sarcoma (FUS) and splicing factor, proline- and glutamine-rich (SFPQ) in human cortical neurons. The spatial dissociation of intranuclear FUS and SFPQ correlates with alternative splicing of the MAPT pre-mRNA and increased tau phosphorylation. Importantly, we show that inducing 4R tau expression using antisense oligonucleotide technology is sufficient to drive neurodegeneration in control human neurons, which phenocopies VCP-mutant neurons. In summary, our findings demonstrate that tau hyperphosphorylation, endolysosomal dysfunction, lysosomal membrane rupture, endoplasmic reticulum stress and apoptosis are driven by a pathogenic increase in 4R tau.
Topics: Humans; Amyotrophic Lateral Sclerosis; Frontotemporal Dementia; Induced Pluripotent Stem Cells; Lysosomes; Valosin Containing Protein
PubMed: 37882537
DOI: 10.1093/brain/awad370 -
European Journal of Pharmacology Aug 2023Ferroptosis was reported to be involved in cerebral ischemia-reperfusion injury (CIRI), on which the effects of berberine (BBR) remain unclear. Moreover, based on the...
Ferroptosis was reported to be involved in cerebral ischemia-reperfusion injury (CIRI), on which the effects of berberine (BBR) remain unclear. Moreover, based on the critical role of gut microbiota in pleiotropic actions of BBR, we hypothesized that BBR can suppress CIRI-induced ferroptosis by modulating the gut microbiota. In this study, the results showed that BBR obviously attenuated the behavioral deficits of CIRI mice, accompanied with the improved survival rate and neuron damages, as phenocopied by dirty cage experiment. The typical morphological changes in ferroptotic cells and biomarkers of ferroptosis were attenuated in BBR- and its fecal microbiota-treated mice, accompanied by reduced malondialdehyde and reactive oxygen species, and the increased glutathione (GSH). BBR was found to alter the gut microbiota of CIRI mice with decreased abundance of Muribaculaceae, Erysipelotrichaceae, Helicobacteraceae, Streptococcaceae and Tannerellaceae, but elevated Bacteroidaceae and Enterobacteriaceae. KEGG analysis based on the 16S rRNA results indicated that multiple metabolic pathways including ferroptosis and GSH metabolism, were altered by BBR. Oppositely, the antibiotics administration counteracted the protective properties of BBR. Summarily, this study revealed the therapeutic potential of BBR on CIRI via inhibiting neuronal ferroptosis, in which upregulated glutathione peroxidase 1 (GPX1) was possibly involved. Moreover, the BBR-modulated gut microbiota was shown to play the critical role in the underlying mechanism.
Topics: Mice; Animals; Berberine; Gastrointestinal Microbiome; RNA, Ribosomal, 16S; Ferroptosis; Ischemia; Reperfusion
PubMed: 37245860
DOI: 10.1016/j.ejphar.2023.175782