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Frontiers in Cell and Developmental... 2021Desmosomes are intercellular junctions, which preserve tissue integrity during homeostatic and stress conditions. These functions rely on their unique structural... (Review)
Review
Desmosomes are intercellular junctions, which preserve tissue integrity during homeostatic and stress conditions. These functions rely on their unique structural properties, which enable them to respond to context-dependent signals and transmit them to change cell behavior. Desmosome composition and size vary depending on tissue specific expression and differentiation state. Their constituent proteins are highly regulated by posttranslational modifications that control their function in the desmosome itself and in addition regulate a multitude of desmosome-independent functions. This review will summarize our current knowledge how signaling pathways that control epithelial shape, polarity and function regulate desmosomes and how desmosomal proteins transduce these signals to modulate cell behavior.
PubMed: 34631720
DOI: 10.3389/fcell.2021.745670 -
Genes Sep 2023Cardiomyopathies (CMPs) represent a significant healthcare burden and are a major cause of heart failure leading to premature death. Several CMPs are now recognized to... (Review)
Review
Cardiomyopathies (CMPs) represent a significant healthcare burden and are a major cause of heart failure leading to premature death. Several CMPs are now recognized to have a strong genetic basis, including arrhythmogenic cardiomyopathy (ACM), which predisposes patients to arrhythmic episodes. Variants in one of the five genes ( and ) encoding proteins of the desmosome are known to cause a subset of ACM, which we classify as desmosome-related ACM (dACM). Phenotypically, this disease may lead to sudden cardiac death in young athletes and, during late stages, is often accompanied by myocardial fibrofatty infiltrates. While the pathogenicity of the desmosome genes has been well established through animal studies and limited supplies of primary human cells, these systems have drawbacks that limit their utility and relevance to understanding human disease. Human induced pluripotent stem cells (hiPSCs) have emerged as a powerful tool for modeling ACM in vitro that can overcome these challenges, as they represent a reproducible and scalable source of cardiomyocytes (CMs) that recapitulate patient phenotypes. In this review, we provide an overview of dACM, summarize findings in other model systems linking desmosome proteins with this disease, and provide an up-to-date summary of the work that has been conducted in hiPSC-cardiomyocyte (hiPSC-CM) models of dACM. In the context of the hiPSC-CM model system, we highlight novel findings that have contributed to our understanding of disease and enumerate the limitations, prospects, and directions for research to consider towards future progress.
Topics: Humans; Induced Pluripotent Stem Cells; Myocytes, Cardiac; Cardiomyopathies; Phenotype
PubMed: 37895213
DOI: 10.3390/genes14101864 -
Current Heart Failure Reports Dec 2021Arrhythmogenic cardiomyopathy (ACM) is a genetic disease characterized by life-threatening ventricular arrhythmias and sudden cardiac death (SCD) in apparently healthy... (Review)
Review
PURPOSE OF REVIEW
Arrhythmogenic cardiomyopathy (ACM) is a genetic disease characterized by life-threatening ventricular arrhythmias and sudden cardiac death (SCD) in apparently healthy young adults. Mutations in genes encoding for cellular junctions can be found in about half of the patients. However, disease onset and severity, risk of arrhythmias, and outcome are highly variable and drug-targeted treatment is currently unavailable.
RECENT FINDINGS
This review focuses on advances in clinical risk stratification, genetic etiology, and pathophysiological concepts. The desmosome is the central part of the disease, but other intercalated disc and associated structural proteins not only broaden the genetic spectrum but also provide novel molecular and cellular insights into the pathogenesis of ACM. Signaling pathways and the role of inflammation will be discussed and targets for novel therapeutic approaches outlined. Genetic discoveries and experimental-driven preclinical research contributed significantly to the understanding of ACM towards mutation- and pathway-specific personalized medicine.
Topics: Arrhythmias, Cardiac; Arrhythmogenic Right Ventricular Dysplasia; Death, Sudden, Cardiac; Heart Failure; Humans; Mutation
PubMed: 34478111
DOI: 10.1007/s11897-021-00532-z -
Kidney International May 2024Desmosomes are multi-protein cell-cell adhesion structures supporting cell stability and mechanical stress resilience of tissues, best described in skin and heart. The...
Desmosomes are multi-protein cell-cell adhesion structures supporting cell stability and mechanical stress resilience of tissues, best described in skin and heart. The kidney is exposed to various mechanical stimuli and stress, yet little is known about kidney desmosomes. In healthy kidneys, we found desmosomal proteins located at the apical-junctional complex in tubular epithelial cells. In four different animal models and patient biopsies with various kidney diseases, desmosomal components were significantly upregulated and partly miss-localized outside of the apical-junctional complexes along the whole lateral tubular epithelial cell membrane. The most upregulated component was desmoglein-2 (Dsg2). Mice with constitutive tubular epithelial cell-specific deletion of Dsg2 developed normally, and other desmosomal components were not altered in these mice. When challenged with different types of tubular epithelial cell injury (unilateral ureteral obstruction, ischemia-reperfusion, and 2,8-dihydroxyadenine crystal nephropathy), we found increased tubular epithelial cell apoptosis, proliferation, tubular atrophy, and inflammation compared to wild-type mice in all models and time points. In vitro, silencing DSG2 via siRNA weakened cell-cell adhesion in HK-2 cells and increased cell death. Thus, our data show a prominent upregulation of desmosomal components in tubular cells across species and diseases and suggest a protective role of Dsg2 against various injurious stimuli.
Topics: Animals; Humans; Mice; Cell Adhesion; Desmoglein 2; Desmosomes; Heart; Kidney Diseases
PubMed: 38395410
DOI: 10.1016/j.kint.2024.01.037 -
Journal of Cardiovascular Translational... Dec 2023The presence of multiple pathogenic variants in desmosomal genes (DSC2, DSG2, DSP, JUP, and PKP2) in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC)...
The presence of multiple pathogenic variants in desmosomal genes (DSC2, DSG2, DSP, JUP, and PKP2) in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) has been linked to a severe phenotype. However, the pathogenicity of variants is reclassified frequently, which may result in a changed clinical risk prediction. Here, we present the collection, reclassification, and clinical outcome correlation for the largest series of ARVC patients carrying multiple desmosomal pathogenic variants to date (n = 331). After reclassification, only 29% of patients remained carriers of two (likely) pathogenic variants. They reached the composite endpoint (ventricular arrhythmias, heart failure, and death) significantly earlier than patients with one or no remaining reclassified variant (hazard ratios of 1.9 and 1.8, respectively). Periodic reclassification of variants contributes to more accurate risk stratification and subsequent clinical management strategy. Graphical Abstract.
Topics: Humans; Arrhythmogenic Right Ventricular Dysplasia; Plakophilins; Phenotype; Arrhythmias, Cardiac; Mutation
PubMed: 37418234
DOI: 10.1007/s12265-023-10403-8 -
Biomedicine & Pharmacotherapy =... Nov 2023Mutant desmoglein 2 (DSG2) is the second most common pathogenic gene in arrhythmogenic cardiomyopathy (ACM), accounting for approximately 10% of ACM cases. In addition... (Review)
Review
Mutant desmoglein 2 (DSG2) is the second most common pathogenic gene in arrhythmogenic cardiomyopathy (ACM), accounting for approximately 10% of ACM cases. In addition to common clinical and pathological features, ACM caused by mutant DSG2 has specific characteristics, manifesting as left ventricle involvement and a high risk of heart failure. Pathological studies have shown extensive cardiomyocyte necrosis, infiltration of immune cells, and fibrofatty replacement in both ventricles, as well as abnormal desmosome structures in the hearts of humans and mice with mutant DSG2-related ACM. Although desmosome dysfunction is a common pathway in the pathogenesis of mutant DSG2-related ACM, the mechanisms underlying this dysfunction vary among mutations. Desmosome dysfunction induces cardiomyocyte injury, plakoglobin dislocation, and gap junction dysfunction, all of which contribute to the initiation and progression of ACM. Additionally, dysregulated inflammation, overactivation of transforming growth factor-beta-1 signaling and endoplasmic reticulum stress, and cardiac metabolic dysfunction contribute to the pathogenesis of ACM caused by mutant DSG2. These features demonstrate that patients with mutant DSG2-related ACM should be managed individually and precisely based on the genotype and phenotype. Further studies are needed to investigate the underlying mechanisms and to identify novel therapies to reverse or attenuate the progression of ACM caused by mutant DSG2.
PubMed: 37696084
DOI: 10.1016/j.biopha.2023.115448 -
The Journal of Dermatology Feb 2023The major autoantigens for pemphigus are desmogleins (Dsgs), cell-cell adhesive structure proteins, one of the desmosomal cadherins. Recent progress in molecular biology... (Review)
Review
The major autoantigens for pemphigus are desmogleins (Dsgs), cell-cell adhesive structure proteins, one of the desmosomal cadherins. Recent progress in molecular biology has revealed that IgG autoantibodies of classical pemphigus react with Dsg1 or Dsg3. Desmocollins (Dscs) also belong to the cadherin supergene family that provides structure to the desmosomes and play an important role in cell-to-cell adhesion. In addition to the presence of four desmosomal Dsg isoforms, i.e. Dsg1-4, Dsc1, 2 and 3, all of which are derived from different genes, Dsc1 has been previously identified as the target antigen of IgA autoantibodies in the subcorneal pustular dermatosis (SPD)-type of intercellular IgA dermatosis. In addition to the IgA anti-Dsc1 autoantiboides, the presence of IgG anti-Dsc autoantibodies is described in patients of some autoimmune bullous diseases. In particular, the current pemphigus detecting autoantibodies to Dscs has shown a tendency in atypical variants of pemphigus. Therefore, autoantibodies against Dscs alone may cause detachment of cell-cell adhesion in the epidermis in some pemphigus. However, except for the findings of a few in vitro and in vivo studies, there is currently no clear evidence for the pathogenicity of anti-Dsc autoantibodies in pemphigus, whereas significance of anti-Dsg autoantibodies is well established. This article describes the structure and function of the Dscs, and explores the evidence regarding the pathogenic role of anti-Dsc autoantibodies in pemphigus.
Topics: Humans; Pemphigus; Autoantibodies; Desmocollins; Skin Diseases, Vesiculobullous; Desmoglein 1; Desmoglein 3; Immunoglobulin A; Immunoglobulin G
PubMed: 36578135
DOI: 10.1111/1346-8138.16660 -
Cells Mar 2022The oral cavity is the gateway for microorganisms into your body where they disseminate not only to the directly connected respiratory and digestive tracts but also to... (Review)
Review
The oral cavity is the gateway for microorganisms into your body where they disseminate not only to the directly connected respiratory and digestive tracts but also to the many remote organs. Oral microbiota, travelling to the end of the intestine and circulating in our bodies through blood vessels, not only affect a gut microbiome profile but also lead to many systemic diseases. By gathering information accumulated from the era of focal infection theory to the age of revolution in microbiome research, we propose a pivotal role of "leaky gum", as an analogy of "leaky gut", to underscore the importance of the oral cavity in systemic health. The oral cavity has unique structures, the gingival sulcus (GS) and the junctional epithelium (JE) below the GS, which are rarely found anywhere else in our body. The JE is attached to the tooth enamel and cementum by hemidesmosome (HD), which is structurally weaker than desmosome and is, thus, vulnerable to microbial infiltration. In the GS, microbial biofilms can build up for life, unlike the biofilms on the skin and intestinal mucosa that fall off by the natural process. Thus, we emphasize that the GS and the JE are the weakest leaky point for microbes to invade the human body, making the leaky gum just as important as, or even more important than, the leaky gut.
Topics: Gastrointestinal Microbiome; Gingiva; Humans; Intestinal Mucosa; Microbiota; Mouth
PubMed: 35406643
DOI: 10.3390/cells11071079 -
Apremilast prevents blistering in human epidermis and stabilizes keratinocyte adhesion in pemphigus.Nature Communications Jan 2023Pemphigus vulgaris is a life-threatening blistering skin disease caused by autoantibodies destabilizing desmosomal adhesion. Current therapies focus on suppression of...
Pemphigus vulgaris is a life-threatening blistering skin disease caused by autoantibodies destabilizing desmosomal adhesion. Current therapies focus on suppression of autoantibody formation and thus treatments directly stabilizing keratinocyte adhesion would fulfill an unmet medical need. We here demonstrate that apremilast, a phosphodiesterase 4 inhibitor used in psoriasis, prevents skin blistering in pemphigus vulgaris. Apremilast abrogates pemphigus autoantibody-induced loss of keratinocyte cohesion in ex-vivo human epidermis, cultured keratinocytes in vitro and in vivo in mice. In parallel, apremilast inhibits keratin retraction as well as desmosome splitting, induces phosphorylation of plakoglobin at serine 665 and desmoplakin assembly into desmosomal plaques. We established a plakoglobin phospho-deficient mouse model that reveals fragile epidermis with altered organization of keratin filaments and desmosomal cadherins. In keratinocytes derived from these mice, intercellular adhesion is impaired and not rescued by apremilast. These data identify an unreported mechanism of desmosome regulation and propose that apremilast stabilizes keratinocyte adhesion and is protective in pemphigus.
Topics: Humans; Mice; Animals; Pemphigus; gamma Catenin; Cell Adhesion; Keratinocytes; Epidermis; Blister; Autoantibodies; Keratins; Desmosomes
PubMed: 36624106
DOI: 10.1038/s41467-022-35741-0 -
Frontiers in Physiology 2020Arrhythmogenic cardiomyopathy has been clinically defined since the 1980s and causes right or biventricular cardiomyopathy associated with ventricular arrhythmia.... (Review)
Review
Arrhythmogenic cardiomyopathy has been clinically defined since the 1980s and causes right or biventricular cardiomyopathy associated with ventricular arrhythmia. Although it is a rare cardiac disease, it is responsible for a significant proportion of sudden cardiac deaths, especially in athletes. The majority of patients with arrhythmogenic cardiomyopathy carry one or more genetic variants in desmosomal genes. In the 1990s, several knockout mouse models of genes encoding for desmosomal proteins involved in cell-cell adhesion revealed for the first time embryonic lethality due to cardiac defects. Influenced by these initial discoveries in mice, arrhythmogenic cardiomyopathy received an increasing interest in human cardiovascular genetics, leading to the discovery of mutations initially in desmosomal genes and later on in more than 25 different genes. Of note, even in the clinic, routine genetic diagnostics are important for risk prediction of patients and their relatives with arrhythmogenic cardiomyopathy. Based on improvements in genetic animal engineering, different transgenic, knock-in, or cardiac-specific knockout animal models for desmosomal and nondesmosomal proteins have been generated, leading to important discoveries in this field. Here, we present an overview about the existing animal models of arrhythmogenic cardiomyopathy with a focus on the underlying pathomechanism and its importance for understanding of this disease. Prospectively, novel mechanistic insights gained from the whole animal, organ, tissue, cellular, and molecular levels will lead to the development of efficient personalized therapies for treatment of arrhythmogenic cardiomyopathy.
PubMed: 32670084
DOI: 10.3389/fphys.2020.00624