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Nature Communications Oct 2023The most prevalent genetic form of inherited arrhythmogenic cardiomyopathy (ACM) is caused by mutations in desmosomal plakophilin-2 (PKP2). By studying pathogenic...
The most prevalent genetic form of inherited arrhythmogenic cardiomyopathy (ACM) is caused by mutations in desmosomal plakophilin-2 (PKP2). By studying pathogenic deletion mutations in the desmosomal protein PKP2, here we identify a general mechanism by which PKP2 delocalization restricts actomyosin network organization and cardiac sarcomeric contraction in this untreatable disease. Computational modeling of PKP2 variants reveals that the carboxy-terminal (CT) domain is required for N-terminal domain stabilization, which determines PKP2 cortical localization and function. In mutant PKP2 cells the expression of the interacting protein MYH10 rescues actomyosin disorganization. Conversely, dominant-negative MYH10 mutant expression mimics the pathogenic CT-deletion PKP2 mutant causing actin network abnormalities and right ventricle systolic dysfunction. A chemical activator of non-muscle myosins, 4-hydroxyacetophenone (4-HAP), also restores normal contractility. Our findings demonstrate that activation of MYH10 corrects the deleterious effect of PKP2 mutant over systolic cardiac contraction, with potential implications for ACM therapy.
Topics: Humans; Arrhythmogenic Right Ventricular Dysplasia; Actomyosin; Mutation; Cardiomyopathies; Plakophilins
PubMed: 37833253
DOI: 10.1038/s41467-023-41981-5 -
Cell and Tissue Research Jun 2015Corneodesmosomes are modified desmosomes present in the stratum corneum (SC). They are crucial for SC cohesion and, thus, constitute one of the pivotal elements of the... (Review)
Review
Corneodesmosomes are modified desmosomes present in the stratum corneum (SC). They are crucial for SC cohesion and, thus, constitute one of the pivotal elements of the functional protective barrier of human skin. Expression of corneodesmosomes and, notably, the process of their degradation are probably altered during several dermatoses leading to the disruption of the permeability barrier or to abnormal, often compensative, SC accumulation. These different situations are reviewed in the present paper.
Topics: Animals; Desmosomes; Epidermis; Genetic Diseases, Inborn; Humans; Models, Biological; Skin Diseases
PubMed: 25378284
DOI: 10.1007/s00441-014-2019-1 -
Upsala Journal of Medical Sciences 2022
Topics: Adenocarcinoma; Carcinoma, Squamous Cell; Desmosomes; Humans; Lung
PubMed: 35140873
DOI: 10.48101/ujms.v127.8250 -
JACC. Basic To Translational Science Jul 2023The authors present a clinical report focused on the overlap between myocarditis and genetic cardiomyopathies of the dilated and arrhythmogenic spectrum. Our cohort was...
The authors present a clinical report focused on the overlap between myocarditis and genetic cardiomyopathies of the dilated and arrhythmogenic spectrum. Our cohort was composed of 25 patients undergoing extensive baseline characterization and prospective reassessment by a dedicated multidisciplinary disease unit during a median follow-up of 69 months. We showed that the use of multimodal imaging allowed both discrimination of specific genotypes and identification of myocardial inflammation proven using endomyocardial biopsy. In addition, we showed that the use of immunomodulatory therapy was beneficial for most patients.
PubMed: 37547072
DOI: 10.1016/j.jacbts.2023.02.018 -
Journal of the American Heart... Jun 2018
Topics: Arrhythmias, Cardiac; Arrhythmogenic Right Ventricular Dysplasia; Cardiomyopathies; Humans
PubMed: 29909403
DOI: 10.1161/JAHA.118.009611 -
Biomedicines Jul 2023The history of arrhythmogenic cardiomyopathy (AC) as a genetically determined desmosomal disease started since the original discovery by Lancisi in a four-generation... (Review)
Review
The history of arrhythmogenic cardiomyopathy (AC) as a genetically determined desmosomal disease started since the original discovery by Lancisi in a four-generation family, published in 1728. Contemporary history at the University of Padua started with Dalla Volta, who haemodynamically investigated patients with "auricularization" of the right ventricle, and with Nava, who confirmed familiarity. The contemporary knowledge advances consisted of (a) AC as a heart muscle disease with peculiar electrical instability of the right ventricle; (b) the finding of pathological substrates, in keeping with a myocardial dystrophy; (c) the inclusion of AC in the cardiomyopathies classification; (d) AC as the main cause of sudden death in athletes; (e) the discovery of the culprit genes coding proteins of the intercalated disc (desmosome); (f) progression in clinical diagnosis with specific ECG abnormalities, angiocardiography, endomyocardial biopsy, 2D echocardiography, electron anatomic mapping and cardiac magnetic resonance; (g) the discovery of left ventricular AC; (h) prevention of SCD with the invention and application of the lifesaving implantable cardioverter defibrillator and external defibrillator scattered in public places and playgrounds as well as the ineligibility for competitive sport activity for AC patients; (i) genetic screening of the proband family to unmask asymptomatic carriers. Nondesmosomal ACs, with a phenotype overlapping desmosomal AC, are also treated, including genetics: Transmembrane protein 43, SCN5A, Desmin, Phospholamban, Lamin A/C, Filamin C, Cadherin 2, Tight junction protein 1.
PubMed: 37509658
DOI: 10.3390/biomedicines11072018 -
Cell Adhesion & Migration Dec 2024Desmosomes are intercellular junctions that regulate mechanical integrity in epithelia and cardiac muscle. Dynamic desmosome remodeling is essential for wound healing...
Desmosomes are intercellular junctions that regulate mechanical integrity in epithelia and cardiac muscle. Dynamic desmosome remodeling is essential for wound healing and development, yet the mechanisms governing junction assembly remain elusive. While we and others have shown that cadherin ectodomains are highly organized, how this ordered architecture emerges during assembly is unknown. Using fluorescence polarization microscopy, we show that desmoglein 2 (Dsg2) ectodomain order gradually increases during 8 h of assembly, coinciding with increasing adhesive strength. In a scratch wound assay, we observed a similar increase in order in desmosomes assembling at the leading edge of migratory cells. Together, our findings indicate that cadherin organization is a hallmark of desmosome maturity and may play a role in conferring adhesive strength.
Topics: Desmosomes; Desmoglein 2; Cadherins; Intercellular Junctions; Cell Adhesion
PubMed: 38566311
DOI: 10.1080/19336918.2024.2333366 -
Journal of Anatomy Jan 2023For electromechanical coupling of cardiomyocytes, intercalated discs (ICDs) are pivotal as highly specialized intercellular contact areas. ICD consists of adhesive... (Review)
Review
For electromechanical coupling of cardiomyocytes, intercalated discs (ICDs) are pivotal as highly specialized intercellular contact areas. ICD consists of adhesive contacts, such as desmosomes and adherens junctions (AJs) that are partially intermingled and thereby form an area composita to provide mechanical strength, as well as gap junctions (GJ) and sodium channels for excitation propagation. In contrast, in epithelia, mixed junctions with features of desmosomes and AJs are regarded as transitory primarily during the formation of desmosomes. The anatomy of desmosomes is defined by a typical ultrastructure with dense intracellular plaques anchoring the cadherin-type adhesion molecules to the intermediate filament cytoskeleton. Desmosomal diseases characterized by impaired adhesive and signalling functions of desmosomal contacts lead to arrhythmogenic cardiomyopathy when affecting cardiomyocytes and cause pemphigus when manifesting in keratinocytes or present as cardiocutaneous syndromes when both cell types are targeted by the disease, which underscores the high biomedical relevance of these cell contacts. Therefore, comparative analyses regarding the structure and regulation of desmosomal contacts in cardiomyocytes and epithelial cells are helpful to better understand disease pathogenesis. In this brief review, we describe the structural properties of ICD compared to epithelial desmosomes and suggest that mechanisms regulating adhesion may at least in part be comparable. Also, we discuss whether phenomena such as hyperadhesion or the bidirectional regulation of desmosomes to serve as signalling hubs in epithelial cells may also be relevant for ICD.
Topics: Desmosomes; Cell Adhesion; Myocardium; Cadherins; Myocytes, Cardiac
PubMed: 35128661
DOI: 10.1111/joa.13634 -
Molecular Biology of the Cell Oct 2021Keratin intermediate filaments form dynamic polymer networks that organize in specific ways dependent on the cell type, the stage of the cell cycle, and the state of the...
Keratin intermediate filaments form dynamic polymer networks that organize in specific ways dependent on the cell type, the stage of the cell cycle, and the state of the cell. In differentiated cells of the epidermis, they are organized by desmosomes, cell-cell adhesion complexes that provide essential mechanical integrity to this tissue. Despite this, we know little about how keratin organization is controlled and whether desmosomes locally regulate keratin dynamics in addition to binding preassembled filaments. Ndel1 is a desmosome-associated protein in the differentiated epidermis, though its function at these structures has not been examined. Here, we show that Ndel1 binds directly to keratin subunits through a motif conserved in all intermediate filament proteins. Further, Ndel1 was necessary for robust desmosome-keratin association and sufficient to reorganize keratins at distinct cellular sites. Lis1, a Ndel1 binding protein, was required for desmosomal localization of Ndel1, but not for its effects on keratin filaments. Finally, we use mouse genetics to demonstrate that loss of Ndel1 results in desmosome defects in the epidermis. Our data thus identify Ndel1 as a desmosome-associated protein that promotes local assembly/reorganization of keratin filaments and is essential for robust desmosome formation.
Topics: 1-Alkyl-2-acetylglycerophosphocholine Esterase; Animals; Carrier Proteins; Cell Adhesion; Cell Differentiation; Cells, Cultured; Cytoskeleton; Desmoplakins; Desmosomes; Epidermal Cells; Epidermis; Intermediate Filaments; Keratinocytes; Keratins; Mice; Microtubule-Associated Proteins
PubMed: 34319758
DOI: 10.1091/mbc.E21-02-0087 -
The Journal of Investigative Dermatology Sep 2016Ca(2+) fluxes direct keratinocyte differentiation, cell-to-cell adhesion, migration, and epidermal barrier homeostasis. We previously showed that intracellular Ca(2+)... (Review)
Review
Ca(2+) fluxes direct keratinocyte differentiation, cell-to-cell adhesion, migration, and epidermal barrier homeostasis. We previously showed that intracellular Ca(2+) stores constitute a major portion of the calcium gradient especially in the stratum granulosum. Loss of the calcium gradient triggers epidermal barrier homeostatic responses. In this report, using unfixed ex vivo epidermis and human epidermal equivalents we show that endoplasmic reticulum (ER) Ca(2+) is released in response to barrier perturbation, and that this release constitutes the major shift in epidermal Ca(2+) seen after barrier perturbation. We find that ER Ca(2+) release correlates with a transient increase in extracellular Ca(2+). Lastly, we show that ER calcium release resulting from barrier perturbation triggers transient desmosomal remodeling, seen as an increase in extracellular space and a loss of the desmosomal intercellular midline. Topical application of thapsigargin, which inhibits the ER Ca(2+) ATPase activity without compromising barrier integrity, also leads to desmosomal remodeling and loss of the midline structure. These experiments establish the ER Ca(2+) store as a master regulator of the Ca(2+) gradient response to epidermal barrier perturbation, and suggest that ER Ca(2+) homeostasis also modulates normal desmosomal reorganization, both at rest and after acute barrier perturbation.
Topics: Animals; Biopsy, Needle; Calcium; Cell Membrane Permeability; Desmosomes; Endoplasmic Reticulum; Epidermis; Homeostasis; Humans; Immunohistochemistry; Skin Absorption; Thapsigargin
PubMed: 27255610
DOI: 10.1016/j.jid.2016.05.100