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1دورية أكاديمية
المؤلفون: Lidya Kristiani, Youngjo Kim
المصدر: Cells, Vol 12, Iss 9, p 1234 (2023)
مصطلحات موضوعية: lamins, laminopathy, HGPS, oxidative stress, DNA damage, senescence, Cytology, QH573-671
الوصف: Oxidative stress is a physiological condition that arises when there is an imbalance between the production of reactive oxygen species (ROS) and the ability of cells to neutralize them. ROS can damage cellular macromolecules, including lipids, proteins, and DNA, leading to cellular senescence and physiological aging. The nuclear lamina (NL) is a meshwork of intermediate filaments that provides structural support to the nucleus and plays crucial roles in various nuclear functions, such as DNA replication and transcription. Emerging evidence suggests that oxidative stress disrupts the integrity and function of the NL, leading to dysregulation of gene expression, DNA damage, and cellular senescence. This review highlights the current understanding of the interplay between oxidative stress and the NL, along with its implications for human health. Specifically, elucidation of the mechanisms underlying the interplay between oxidative stress and the NL is essential for the development of effective treatments for laminopathies and age-related diseases.
وصف الملف: electronic resource
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2دورية أكاديمية
المصدر: Cells, Vol 9, Iss 8, p 1884 (2020)
مصطلحات موضوعية: nuclear lamina, mechanosensing, mechanoresponse, nuclear rupture, nuclear stiffness, laminopathy, Cytology, QH573-671
الوصف: The nuclear lamins are the major components of the nuclear lamina in the nuclear envelope. Lamins are involved in numerous functions, including a role in providing structural support to the cell and the mechanosensing of the cell. Mutations in the genes encoding for lamins lead to the rare diseases termed laminopathies. However, not only laminopathies show alterations in the nuclear lamina. Deregulation of lamin expression is reported in multiple cancers and several viral infections lead to a disrupted nuclear lamina. The structural and mechanical effects of alterations in the nuclear lamina can partly explain the phenotypes seen in disease, such as muscular weakness in certain laminopathies and transmigration of cancer cells. However, a lot of answers to questions about the relation between changes in the nuclear lamina and disease development remain elusive. Here, we review the current understandings of the contribution of the nuclear lamina in the structural support and mechanosensing of healthy and diseased cells.
وصف الملف: electronic resource
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3دورية أكاديمية
المؤلفون: Déborah Gómez-Domínguez, Carolina Epifano, Fernando de Miguel, Albert García Castaño, Borja Vilaplana-Martí, Alberto Martín, Sandra Amarilla-Quintana, Anne T Bertrand, Gisèle Bonne, Javier Ramón-Azcón, Miguel A Rodríguez-Milla, Ignacio Pérez de Castro
المصدر: Cells, Vol 9, Iss 5, p 1286 (2020)
مصطلحات موضوعية: LMNA, laminopathy, CRISPR, nuclear envelope, Cytology, QH573-671
الوصف: Laminopathies are causally associated with mutations on the Lamin A/C gene (LMNA). To date, more than 400 mutations in LMNA have been reported in patients. These mutations are widely distributed throughout the entire gene and are associated with a wide range of phenotypes. Unfortunately, little is known about the mechanisms underlying the effect of the majority of these mutations. This is the case of more than 40 mutations that are located at exon 4. Using CRISPR/Cas9 technology, we generated a collection of Lmna exon 4 mutants in mouse C2C12 myoblasts. These cell models included different types of exon 4 deletions and the presence of R249W mutation, one of the human variants associated with a severe type of laminopathy, LMNA-associated congenital muscular dystrophy (L-CMD). We characterized these clones by measuring their nuclear circularity, myogenic differentiation capacity in 2D and 3D conditions, DNA damage, and levels of p-ERK and p-AKT (phosphorylated Mitogen-Activated Protein Kinase 1/3 and AKT serine/threonine kinase 1). Our results indicated that Lmna exon 4 mutants showed abnormal nuclear morphology. In addition, levels and/or subcellular localization of different members of the lamin and LINC (LInker of Nucleoskeleton and Cytoskeleton) complex were altered in all these mutants. Whereas no significant differences were observed for ERK and AKT activities, the accumulation of DNA damage was associated to the Lmna p.R249W mutant myoblasts. Finally, significant myogenic differentiation defects were detected in the Lmna exon 4 mutants. These results have key implications in the development of future therapeutic strategies for the treatment of laminopathies.
وصف الملف: electronic resource
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4دورية أكاديمية
المصدر: Cells, Vol 9, Iss 5, p 1306 (2020)
مصطلحات موضوعية: lamin A/C, mechanotransduction, laminopathy, gene regulation, lamin partners, Hutchinson Gilford progeria syndrome, Cytology, QH573-671
الوصف: Mechanotransduction translates forces into biological responses and regulates cell functionalities. It is implicated in several diseases, including laminopathies which are pathologies associated with mutations in lamins and lamin-associated proteins. These pathologies affect muscle, adipose, bone, nerve, and skin cells and range from muscular dystrophies to accelerated aging. Although the exact mechanisms governing laminopathies and gene expression are still not clear, a strong correlation has been found between cell functionality and nuclear behavior. New theories base on the direct effect of external force on the genome, which is indeed sensitive to the force transduced by the nuclear lamina. Nuclear lamina performs two essential functions in mechanotransduction pathway modulating the nuclear stiffness and governing the chromatin remodeling. Indeed, A-type lamin mutation and deregulation has been found to affect the nuclear response, altering several downstream cellular processes such as mitosis, chromatin organization, DNA replication-transcription, and nuclear structural integrity. In this review, we summarize the recent findings on the molecular composition and architecture of the nuclear lamina, its role in healthy cells and disease regulation. We focus on A-type lamins since this protein family is the most involved in mechanotransduction and laminopathies.
وصف الملف: electronic resource
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5دورية أكاديمية
المؤلفون: Jungwon Hah, Dong-Hwee Kim
المصدر: Cells, Vol 8, Iss 3, p 231 (2019)
مصطلحات موضوعية: lamin, laminopathy, cytoskeleton, nucleus, Cytology, QH573-671
الوصف: Extracellular mechanical stimuli are translated into biochemical signals inside the cell via mechanotransduction. The nucleus plays a critical role in mechanoregulation, which encompasses mechanosensing and mechanotransduction. The nuclear lamina underlying the inner nuclear membrane not only maintains the structural integrity, but also connects the cytoskeleton to the nuclear envelope. Lamin mutations, therefore, dysregulate the nuclear response, resulting in abnormal mechanoregulations, and ultimately, disease progression. Impaired mechanoregulations even induce malfunction in nuclear positioning, cell migration, mechanosensation, as well as differentiation. To know how to overcome laminopathies, we need to understand the mechanisms of laminopathies in a mechanobiological way. Recently, emerging studies have demonstrated the varying defects from lamin mutation in cellular homeostasis within mechanical surroundings. Therefore, this review summarizes recent findings highlighting the role of lamins, the architecture of nuclear lamina, and their disease relevance in the context of nuclear mechanobiology. We will also provide an overview of the differentiation of cellular mechanics in laminopathy.
وصف الملف: electronic resource
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6دورية أكاديمية
المؤلفون: Magda Dubińska-Magiera, Katarzyna Kozioł, Magdalena Machowska, Katarzyna Piekarowicz, Daria Filipczak, Ryszard Rzepecki
المصدر: Cells, Vol 8, Iss 3, p 240 (2019)
مصطلحات موضوعية: emerin, EDMD1, lamin, laminopathy, lamin A/C, LAP2β, tubulin, mitotic spindle, Cytology, QH573-671
الوصف: Emerin is an essential LEM (LAP2, Emerin, MAN1) domain protein in metazoans and an integral membrane protein associated with inner and outer nuclear membranes. Mutations in the human EMD gene coding for emerin result in the rare genetic disorder: Emery–Dreifuss muscular dystrophy type 1 (EDMD1). This disease belongs to a broader group called laminopathies—a heterogeneous group of rare genetic disorders affecting tissues of mesodermal origin. EDMD1 phenotype is characterized by progressive muscle wasting, contractures of the elbow and Achilles tendons, and cardiac conduction defects. Emerin is involved in many cellular and intranuclear processes through interactions with several partners: lamins; barrier-to-autointegration factor (BAF), β-catenin, actin, and tubulin. Our study demonstrates the presence of the emerin fraction which associates with mitotic spindle microtubules and centrosomes during mitosis and colocalizes during early mitosis with lamin A/C, BAF, and membranes at the mitotic spindle. Transfection studies with cells expressing EGFP-emerin protein demonstrate that the emerin fusion protein fraction also localizes to centrosomes and mitotic spindle microtubules during mitosis. Transient expression of emerin deletion mutants revealed that the resulting phenotypes vary and are mutant dependent. The most frequent phenotypes include aberrant nuclear shape, tubulin network mislocalization, aberrant mitosis, and mislocalization of centrosomes. Emerin deletion mutants demonstrated different chromatin binding capacities in an in vitro nuclear assembly assay and chromatin-binding properties correlated with the strength of phenotypic alteration in transfected cells. Aberrant tubulin staining and microtubule network phenotype appearance depended on the presence of the tubulin binding region in the expressed deletion mutants. We believe that the association with tubulin might help to “deliver” emerin and associated membranes to decondensing chromatin. Preliminary analyses of cells from Polish patients with EDMD1 revealed that for several mutations thought to be null for emerin protein, a truncated emerin protein was present. We infer that the EDMD1 phenotype may be strengthened by the toxicity of truncated emerin expressed in patients with certain nonsense mutations in EMD.
وصف الملف: electronic resource
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7دورية أكاديمية
المصدر: Cells, Vol 8, Iss 2, p 88 (2019)
مصطلحات موضوعية: HGPS, laminopathy, lamin A/C, progerin, gene therapy, miR9, Cytology, QH573-671
الوصف: Hutchinson-Gilford progeria syndrome (HGPS) is one of the most severe disorders among laminopathies—a heterogeneous group of genetic diseases with a molecular background based on mutations in the LMNA gene and genes coding for interacting proteins. HGPS is characterized by the presence of aging-associated symptoms, including lack of subcutaneous fat, alopecia, swollen veins, growth retardation, age spots, joint contractures, osteoporosis, cardiovascular pathology, and death due to heart attacks and strokes in childhood. LMNA codes for two major, alternatively spliced transcripts, give rise to lamin A and lamin C proteins. Mutations in the LMNA gene alone, depending on the nature and location, may result in the expression of abnormal protein or loss of protein expression and cause at least 11 disease phenotypes, differing in severity and affected tissue. LMNA gene-related HGPS is caused by a single mutation in the LMNA gene in exon 11. The mutation c.1824C > T results in activation of the cryptic donor splice site, which leads to the synthesis of progerin protein lacking 50 amino acids. The accumulation of progerin is the reason for appearance of the phenotype. In this review, we discuss current knowledge on the molecular mechanisms underlying the development of HGPS and provide a critical analysis of current research trends in this field. We also discuss the mouse models available so far, the current status of treatment of the disease, and future prospects for the development of efficient therapies, including gene therapy for HGPS.
وصف الملف: electronic resource
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8
المؤلفون: Gisèle Bonne, Anne Bertrand, Carolina Epifano, Javier Ramón-Azcón, Alberto Martín, Albert G. Castaño, Miguel Ángel Rodríguez-Milla, Déborah Gómez-Domínguez, Fernando de Miguel, Borja Vilaplana-Martí, Sandra Amarilla-Quintana, Ignacio Pérez de Castro
المساهمون: Ministerio de Ciencia e Innovación (España), Instituto de Salud Carlos III, Instituto de Salud Carlos III [Madrid] (ISC), Universidad Europea de Madrid, Institute for Bioengineering of Catalonia [Barcelona] (IBEC), Institut de Myologie, Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Association française contre les myopathies (AFM-Téléthon)-Sorbonne Université (SU), Centre de Recherche en Myologie, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Institució Catalana de Recerca i Estudis Avançats (ICREA), Centre de recherche en Myologie – U974 SU-INSERM
المصدر: Cells
Repisalud
Instituto de Salud Carlos III (ISCIII)
Cells, MDPI, 2020, 9 (5), pp.1286. ⟨10.3390/cells9051286⟩
Cells, Vol 9, Iss 1286, p 1286 (2020)
ABACUS. Repositorio de Producción Científica
Universidad Europea (UEM)
Volume 9
Issue 5مصطلحات موضوعية: life_sciences_other, 0301 basic medicine, Laminopathy, [SDV]Life Sciences [q-bio], Mutant, laminopathy, medicine.disease_cause, Muscle Development, LMNA, Myoblasts, Exon, Mice, 0302 clinical medicine, Tecnología médica, lcsh:QH301-705.5, Genetics, Mutation, integumentary system, Cell Differentiation, General Medicine, nuclear envelope, Exons, Lamin Type A, 030220 oncology & carcinogenesis, CRISPR, Female, C2C12, Microtubule-Associated Proteins, Subcellular Fractions, congenital, hereditary, and neonatal diseases and abnormalities, Cell Nucleus Shape, Membrana nuclear, Nuclear Envelope, MAP Kinase Signaling System, Telomere-Binding Proteins, Biology, Distrofias musculares, Article, Cell Line, 03 medical and health sciences, medicine, Animals, Protein kinase B, Cell Nucleus, Biología celular, Base Sequence, Membrane Proteins, medicine.disease, Genética, Clone Cells, 030104 developmental biology, lcsh:Biology (General), Lamin, DNA Damage
الوصف: Laminopathies are causally associated with mutations on the Lamin A/C gene (LMNA). To date, more than 400 mutations in LMNA have been reported in patients. These mutations are widely distributed throughout the entire gene and are associated with a wide range of phenotypes. Unfortunately, little is known about the mechanisms underlying the effect of the majority of these mutations. This is the case of more than 40 mutations that are located at exon 4. Using CRISPR/Cas9 technology, we generated a collection of Lmna exon 4 mutants in mouse C2C12 myoblasts. These cell models included different types of exon 4 deletions and the presence of R249W mutation, one of the human variants associated with a severe type of laminopathy, LMNA-associated congenital muscular dystrophy (L-CMD). We characterized these clones by measuring their nuclear circularity, myogenic differentiation capacity in 2D and 3D conditions, DNA damage, and levels of p-ERK and p-AKT (phosphorylated Mitogen-Activated Protein Kinase 1/3 and AKT serine/threonine kinase 1). Our results indicated that Lmna exon 4 mutants showed abnormal nuclear morphology. In addition, levels and/or subcellular localization of different members of the lamin and LINC (LInker of Nucleoskeleton and Cytoskeleton) complex were altered in all these mutants. Whereas no significant differences were observed for ERK and AKT activities, the accumulation of DNA damage was associated to the Lmna p.R249W mutant myoblasts. Finally, significant myogenic differentiation defects were detected in the Lmna exon 4 mutants. These results have key implications in the development of future therapeutic strategies for the treatment of laminopathies. Ministerio de Ciencia e Innovación (Acción estratégica en Salud intramural PI16III/00017-TPY1348/16). Fundación Andrés Marcio, niños contra la laminopatía (TPY-259/19). 6.600 JCR (2020) Q2, 53/195 Cell Biology 1.220 SJR (2020) Q1, 51/254 Biochemistry, Genetics and Molecular Biology (miscellaneous) No data IDR 2020 UEM
وصف الملف: application/pdf
الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::0ee86261be732949b99b100fed582abbTest
http://europepmc.org/articles/PMC7291140Test -
9دورية أكاديمية
المؤلفون: Damien Galant, Bénédicte Gaborit, Camille Desgrouas, Ines Abdesselam, Monique Bernard, Nicolas Levy, Françoise Merono, Catherine Coirault, Patrice Roll, Arnaud Lagarde, Nathalie Bonello-Palot, Patrice Bourgeois, Anne Dutour, Catherine Badens
المصدر: Cells, Vol 5, Iss 2, p 21 (2016)
مصطلحات موضوعية: metabolic syndrome, cardiomyopathy, ZMPSTE24, premature senescence, nuclear anomalies, laminopathy, Cytology, QH573-671
الوصف: ZMPSTE24 encodes the only metalloprotease, which transforms prelamin into mature lamin A. Up to now, mutations in ZMPSTE24 have been linked to Restrictive Dermopathy (RD), Progeria or Mandibulo-Acral Dysplasia (MAD). We report here the phenotype of a patient referred for severe metabolic syndrome and cardiomyopathy, carrying a mutation in ZMPSTE24. The patient presented with a partial lipodystrophic syndrome associating hypertriglyceridemia, early onset type 2 diabetes, and android obesity with truncal and abdominal fat accumulation but without subcutaneous lipoatrophy. Other clinical features included acanthosis nigricans, liver steatosis, dilated cardiomyopathy, and high myocardial and hepatic triglycerides content. Mutated fibroblasts from the patient showed increased nuclear shape abnormalities and premature senescence as demonstrated by a decreased Population Doubling Level, an increased beta-galactosidase activity and a decreased BrdU incorporation rate. Reduced prelamin A expression by siRNA targeted toward LMNA transcripts resulted in decreased nuclear anomalies. We show here that a central obesity without subcutaneous lipoatrophy is associated with a laminopathy due to a heterozygous missense mutation in ZMPSTE24. Given the high prevalence of metabolic syndrome and android obesity in the general population, and in the absence of familial study, the causative link between mutation and phenotype cannot be formally established. Nevertheless, altered lamina architecture observed in mutated fibroblasts are responsible for premature cellular senescence and could contribute to the phenotype observed in this patient.
وصف الملف: electronic resource
النص الكامل