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BMJ Case Reports Sep 2023
Topics: Humans; Progeria
PubMed: 37723091
DOI: 10.1136/bcr-2023-256203 -
FEBS Letters Nov 2023Nuclear lamins are type-V intermediate filaments that are involved in many nuclear processes. In mammals, A- and B-type lamins assemble into separate physical meshwork... (Review)
Review
Nuclear lamins are type-V intermediate filaments that are involved in many nuclear processes. In mammals, A- and B-type lamins assemble into separate physical meshwork underneath the inner nuclear membrane, the nuclear lamina, with some residual fraction localized within the nucleoplasm. Lamins are the major part of the nucleoskeleton, providing mechanical strength and flexibility to protect the genome and allow nuclear deformability, while also contributing to gene regulation via interactions with chromatin. While lamins are the evolutionary ancestors of all intermediate filament family proteins, their ultimate filamentous assembly is markedly different from their cytoplasmic counterparts. Interestingly, hundreds of genetic mutations in the lamina proteins have been causally linked with a broad range of human pathologies, termed laminopathies. These include muscular, neurological and metabolic disorders, as well as premature aging diseases. Recent technological advances have contributed to resolving the filamentous structure of lamins and the corresponding lamina organization. In this review, we revisit the multiscale lamin organization and discuss its implications on nuclear mechanics and chromatin organization within lamina-associated domains.
Topics: Animals; Humans; Nuclear Lamina; Intermediate Filaments; Lamins; Cell Nucleus; Chromatin; Nuclear Envelope; Mammals
PubMed: 37813648
DOI: 10.1002/1873-3468.14750 -
Mechanisms of Ageing and Development Dec 2023Hutchinson-Gilford progeria syndrome (HGPS), also known as hereditary progeria syndrome, is caused by mutations in the LMNA gene and the expression of progerin, which...
Hutchinson-Gilford progeria syndrome (HGPS), also known as hereditary progeria syndrome, is caused by mutations in the LMNA gene and the expression of progerin, which causes accelerated aging and premature death, with most patients dying of heart failure or other cardiovascular complications in their teens. HGPS patients are able to exhibit cardiovascular phenotypes similar to physiological aging, such as extensive atherosclerosis, smooth muscle cell loss, vascular lesions, and electrical and functional abnormalities of the heart. It also excludes the traditional risk causative factors of cardiovascular disease, making HGPS a new model for studying aging-related cardiovascular disease. Here, we analyzed the pathogenesis and pathophysiological characteristics of HGPS and the relationship between HGPS and cardiovascular disease, provided insight into the molecular mechanisms of cardiovascular disease pathogenesis in HGPS patients and treatment strategies for this disease. Moreover, we summarize the disease models used in HGPS studies to improve our understanding of the pathological mechanisms of cardiovascular aging in HGPS patients.
Topics: Humans; Adolescent; Progeria; Cardiovascular Diseases; Aging; Atherosclerosis; Cardiovascular System
PubMed: 37832833
DOI: 10.1016/j.mad.2023.111879 -
Cells Jul 2019The eukaryotic nucleus controls most cellular processes. It is isolated from the cytoplasm by the nuclear envelope, which plays a prominent role in the structural... (Review)
Review
The eukaryotic nucleus controls most cellular processes. It is isolated from the cytoplasm by the nuclear envelope, which plays a prominent role in the structural organization of the cell, including nucleocytoplasmic communication, chromatin positioning, and gene expression. Alterations in nuclear composition and function are eminently pronounced upon stress and during premature and physiological aging. These alterations are often accompanied by epigenetic changes in histone modifications. We review, here, the role of nuclear envelope proteins and histone modifiers in the 3-dimensional organization of the genome and the implications for gene expression. In particular, we focus on the nuclear lamins and the chromatin-associated protein BAF, which are linked to Hutchinson-Gilford and Nestor-Guillermo progeria syndromes, respectively. We also discuss alterations in nuclear organization and the epigenetic landscapes during normal aging and various stress conditions, ranging from yeast to humans.
Topics: Aging; Chromatin; DNA-Binding Proteins; Epigenesis, Genetic; Histone Code; Histones; Humans; Lamins; Nuclear Lamina; Progeria; Stress, Physiological
PubMed: 31266244
DOI: 10.3390/cells8070664 -
Genes Feb 2023Hutchinson-Gilford progeria syndrome (HGPS) is a rare, autosomal-dominant, and fatal premature aging syndrome. HGPS is most often derived from a de novo point mutation... (Review)
Review
Hutchinson-Gilford progeria syndrome (HGPS) is a rare, autosomal-dominant, and fatal premature aging syndrome. HGPS is most often derived from a de novo point mutation in the gene, which results in an alternative splicing defect and the generation of the mutant protein, progerin. Progerin behaves in a dominant-negative fashion, leading to a variety of cellular and molecular changes, including nuclear abnormalities, defective DNA damage response (DDR) and DNA repair, and accelerated telomere attrition. Intriguingly, many of the manifestations of the HGPS cells are shared with normal aging cells. However, at a clinical level, HGPS does not fully match normal aging because of the accelerated nature of the phenotypes and its primary effects on connective tissues. Furthermore, the epigenetic changes in HGPS patients are of great interest and may play a crucial role in the pathogenesis of HGPS. Finally, various treatments for the HGPS patients have been developed in recent years with important effects at a cellular level, which translate to symptomatic improvement and increased lifespan.
Topics: Humans; Progeria; Cellular Senescence; Cell Nucleus; Epigenesis, Genetic
PubMed: 36980874
DOI: 10.3390/genes14030602 -
Cells May 2020Mechanotransduction translates forces into biological responses and regulates cell functionalities. It is implicated in several diseases, including laminopathies which... (Review)
Review
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.
Topics: Animals; Humans; Lamin Type A; Laminopathies; Mechanotransduction, Cellular; Mutation; Protein Binding
PubMed: 32456328
DOI: 10.3390/cells9051306 -
Sub-cellular Biochemistry 2023Development from embryo to adult, organismal homeostasis and ageing are consecutive processes that rely on several functions of the nuclear envelope (NE). The NE...
Development from embryo to adult, organismal homeostasis and ageing are consecutive processes that rely on several functions of the nuclear envelope (NE). The NE compartmentalises the eukaryotic cells and provides physical stability to the genetic material in the nucleus. It provides spatiotemporal regulation of gene expression by controlling nuclear import and hence access of transcription factors to target genes as well as organisation of the genome into open and closed compartments. In addition, positioning of chromatin relative to the NE is important for DNA replication and repair and thereby also for genome stability. We discuss here the relevance of the NE in two classes of age-related human diseases. Firstly, we focus on the progeria syndromes Hutchinson-Gilford (HGPS) and Nestor-Guillermo (NGPS), which are caused by mutations in the LMNA and BANF1 genes, respectively. Both genes encode ubiquitously expressed components of the nuclear lamina that underlines the nuclear membranes. HGPS and NGPS patients manifest symptoms of accelerated ageing and cells from affected individuals show similar defects as cells from healthy old donors, including signs of increased DNA damage and epigenetic alternations. Secondly, we describe how several age-related neurodegenerative diseases, such as amyotrophic lateral sclerosis and Huntington's disease, are related with defects in nucleocytoplasmic transport. A common feature of this class of diseases is the accumulation of nuclear pore proteins and other transport factors in inclusions. Importantly, genetic manipulations of the nucleocytoplasmic transport machinery can alleviate disease-related phenotypes in cell and animal models, paving the way for potential therapeutic interventions.
Topics: Adult; Animals; Humans; Aging; Cell Nucleus; Chromatin; Nuclear Envelope; Progeria
PubMed: 36600129
DOI: 10.1007/978-3-031-21410-3_3 -
Journal of Atherosclerosis and... Apr 2022Hutchinson-Gilford progeria syndrome (HGPS) and Werner syndrome (WS) are two of the representative genetic progeroid syndromes and have been widely studied in the field... (Review)
Review
Hutchinson-Gilford progeria syndrome (HGPS) and Werner syndrome (WS) are two of the representative genetic progeroid syndromes and have been widely studied in the field of aging research. HGPS is a pediatric disease in which premature aging symptoms appear in early childhood, and death occurs at an average age of 14.5 years, mainly due to cardiovascular disease (CVD). Conversely, WS patients exhibit accelerated aging phenotypes after puberty and die in their 50s due to CVD and malignant tumors. Both diseases are models of human aging, leading to a better understanding of the aging-associated development of CVD. In this review, we discuss the pathogenesis and treatment of atherosclerotic diseases presented by both progeroid syndromes with the latest findings.
Topics: Aging; Atherosclerosis; Cardiovascular Diseases; Child, Preschool; Humans; Progeria; Werner Syndrome
PubMed: 34511576
DOI: 10.5551/jat.RV17061 -
Journal of Cellular Physiology Apr 2020Converging evidence indicates the dysregulation of unique cytosolic compartments called stress granules (SGs) might facilitate the accumulation of toxic protein... (Review)
Review
Converging evidence indicates the dysregulation of unique cytosolic compartments called stress granules (SGs) might facilitate the accumulation of toxic protein aggregates that underlie many age-related neurodegenerative pathologies (ANPs). SG dynamics are particularly susceptible to the cellular conditions that are commonly induced by aging, including the elevation in reactive oxygen species and increased concentration of aggregate-prone proteins. In turn, the persistent formation of these compartments is hypothesized to serve as a seed for subsequent protein aggregation. Notably, the protein quality control (PQC) machinery responsible for inhibiting persistent SGs (e.g., Hsc70-BAG3) can become compromised with age, suggesting that the modulation of such PQC mechanisms could reliably inhibit pathological processes of ANPs. As exemplified in the context of accelerated aging syndromes (i.e., Hutchinson-Gilford progeria), PQC enhancement is emerging as a potential therapeutic strategy, indicating similar techniques might be applied to ANPs. Collectively, these recent findings advance our understanding of how the processes that might facilitate protein aggregation are particularly susceptible to aging conditions, and present investigators with an opportunity to develop novel targets for ANPs.
Topics: Adaptor Proteins, Signal Transducing; Aging; Animals; Apoptosis Regulatory Proteins; Humans; Neurodegenerative Diseases; Reactive Oxygen Species; Stress, Physiological
PubMed: 31556109
DOI: 10.1002/jcp.29248