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Annual Review of Cell and Developmental... Oct 2021The cell nucleus is best known as the container of the genome. Its envelope provides a barrier for passive macromolecule diffusion, which enhances the control of gene... (Review)
Review
The cell nucleus is best known as the container of the genome. Its envelope provides a barrier for passive macromolecule diffusion, which enhances the control of gene expression. As its largest and stiffest organelle, the nucleus also defines the minimal space requirements of a cell. Internal or external pressures that deform a cell to its physical limits cause a corresponding nuclear deformation. Evidence is consolidating that the nucleus, in addition to its genetic functions, serves as a physical sensing device for critical cell body deformation. Nuclear mechanotransduction allows cells to adapt their acute behaviors, mechanical stability, paracrine signaling, and fate to their physical surroundings. This review summarizes the basic chemical and mechanical properties of nuclear components, and how these properties are thought to be utilized for mechanosensing.
Topics: Cell Nucleus; Mechanotransduction, Cellular
PubMed: 34213953
DOI: 10.1146/annurev-cellbio-120319-030049 -
The Journal of Cell Biology Jan 2024Mutations in genes encoding nuclear lamins cause diseases called laminopathies. In this issue, Hasper et al. (https://doi.org/10.1083/jcb.202307049) show that lamin A/C...
Mutations in genes encoding nuclear lamins cause diseases called laminopathies. In this issue, Hasper et al. (https://doi.org/10.1083/jcb.202307049) show that lamin A/C and the prelamin A variant in Hutchinson-Gilford progeria syndrome have relatively long lifetimes in affected tissues.
Topics: Humans; Lamins; Lamin Type A; Nuclear Lamina; Progeria
PubMed: 38078930
DOI: 10.1083/jcb.202311193 -
Circulation Jul 2018
Topics: Animals; Atherosclerosis; Lamin Type A; Mice; Muscle, Smooth, Vascular; Progeria
PubMed: 30012702
DOI: 10.1161/CIRCULATIONAHA.118.034480 -
Trends in Cell Biology Feb 2020Mounting evidence suggests that DNA damage plays a central role in aging. Multiple tiers of defense have evolved to reduce the accumulation of DNA damage, including... (Review)
Review
Mounting evidence suggests that DNA damage plays a central role in aging. Multiple tiers of defense have evolved to reduce the accumulation of DNA damage, including reducing damaging molecules, repairing DNA damage, and inducing senescence or apoptosis in response to persistent DNA damage. Mutations in or failure of these pathways can lead to accelerated or premature aging and age-related decline in vital organs, supporting the hypothesis that maintaining a pristine genome is paramount for human health. Understanding how we cope with DNA damage could inform on the aging process and further on how deficient DNA maintenance manifests in age-related phenotypes. This knowledge may lead to the development of novel interventions promoting healthspan.
Topics: Aging; Animals; Cellular Senescence; DNA Damage; DNA Repair; Genome; Humans; Mutation
PubMed: 31917080
DOI: 10.1016/j.tcb.2019.12.001 -
Aging Dec 2019
Topics: Animals; Humans; Progeria
PubMed: 31866585
DOI: 10.18632/aging.102626 -
Indian Journal of Clinical Biochemistry... Jan 2020An uncommon deadly genetic situation symbolized by the presence of rapid maturation in infants is called as the Hutchinson-Gilford Progeria Syndrome. The term basically... (Review)
Review
An uncommon deadly genetic situation symbolized by the presence of rapid maturation in infants is called as the Hutchinson-Gilford Progeria Syndrome. The term basically is meant as 'prematurely old' taken from the Greek meanings. The selective cause behind this syndrome is usually a mutation in a gene called LMNA. The product of this LMNA gene which is a protein i.e. Lamin-A is considered to be responsible for anatomical framing which clasps the nuclei of the cell, well organized and together. But, the recent investigations prove a deformity in the protein i.e. Lamin-A that leads to the non-stability of the nuclei an thus gives rise to the deadly situation of untimely ageing in the children popularly known as Progeria. The literature review investigation provided pivotal information about the therapeutic researches related to the syndrome, the mutational causes and the basic information including the major and minor symptoms generally shown by the patients affected with Hutchinson-Gilford Progeria Syndrome. Investigations on this rare, uncommon disease i.e. Progeria had begun a couple of years back and in some of the researches many important aspects about the causes and possible curative drugs related to the disease which can help the patients in leading a normal life with lesser side effects and symptoms have also been discussed. Further studies will more clearly clarify the possible curative agents and unrevealed mechanisms of the disease which will help the scientists to develop measures which can provide more beneficial and healthy life to the patients with lesser complications.
PubMed: 32071491
DOI: 10.1007/s12291-019-00849-6 -
Circulation Nov 2021Hutchinson-Gilford progeria syndrome (HGPS) is a rare disorder characterized by premature aging and death mainly because of myocardial infarction, stroke, or heart...
BACKGROUND
Hutchinson-Gilford progeria syndrome (HGPS) is a rare disorder characterized by premature aging and death mainly because of myocardial infarction, stroke, or heart failure. The disease is provoked by progerin, a variant of lamin A expressed in most differentiated cells. Patients look healthy at birth, and symptoms typically emerge in the first or second year of life. Assessing the reversibility of progerin-induced damage and the relative contribution of specific cell types is critical to determining the potential benefits of late treatment and to developing new therapies.
METHODS
We used CRISPR-Cas9 technology to generate () mice engineered to ubiquitously express progerin while lacking lamin A and allowing progerin suppression and lamin A restoration in a time- and cell type-specific manner on Cre recombinase activation. We characterized the phenotype of mice and crossed them with Cre transgenic lines to assess the effects of suppressing progerin and restoring lamin A ubiquitously at different disease stages as well as specifically in vascular smooth muscle cells and cardiomyocytes.
RESULTS
Like patients with HGPS, mice appear healthy at birth and progressively develop HGPS symptoms, including failure to thrive, lipodystrophy, vascular smooth muscle cell loss, vascular fibrosis, electrocardiographic anomalies, and precocious death (median lifespan of 15 months versus 26 months in wild-type controls, <0.0001). Ubiquitous progerin suppression and lamin A restoration significantly extended lifespan when induced in 6-month-old mildly symptomatic mice and even in severely ill animals aged 13 months, although the benefit was much more pronounced on early intervention (84.5% lifespan extension in mildly symptomatic mice, <0.0001, and 6.7% in severely ill mice, <0.01). It is remarkable that major vascular alterations were prevented and lifespan normalized in mice when progerin suppression and lamin A restoration were restricted to vascular smooth muscle cells and cardiomyocytes.
CONCLUSIONS
mice constitute a new experimental model for advancing knowledge of HGPS. Our findings suggest that it is never too late to treat HGPS, although benefit is much more pronounced when progerin is targeted in mice with mild symptoms. Despite the broad expression pattern of progerin and its deleterious effects in many organs, restricting its suppression to vascular smooth muscle cells and cardiomyocytes is sufficient to prevent vascular disease and normalize lifespan.
Topics: Animals; Disease Models, Animal; Humans; Lamin Type A; Mice; Mice, Transgenic; Muscle, Smooth, Vascular; Myocytes, Cardiac; Myocytes, Smooth Muscle; Progeria
PubMed: 34694158
DOI: 10.1161/CIRCULATIONAHA.121.055313 -
Aging Oct 2018
Topics: Animals; Atherosclerosis; Disease Models, Animal; Lamin Type A; Mice; Muscle, Smooth, Vascular; Progeria
PubMed: 30348906
DOI: 10.18632/aging.101608 -
Aging Aug 2020
Topics: Cellular Senescence; Humans; Sirolimus; Stem Cells; TOR Serine-Threonine Kinases
PubMed: 32756013
DOI: 10.18632/aging.103816 -
Nucleus (Austin, Tex.) Dec 2023As human longevity increases, understanding the molecular mechanisms that drive aging becomes ever more critical to promote health and prevent age-related disorders.... (Review)
Review
As human longevity increases, understanding the molecular mechanisms that drive aging becomes ever more critical to promote health and prevent age-related disorders. Premature aging disorders or progeroid syndromes can provide critical insights into aspects of physiological aging. A major cause of progeroid syndromes which result from mutations in the genes and is disruption of the final posttranslational processing step in the production of the nuclear scaffold protein lamin A. encodes the lamin A precursor, prelamin A and encodes the prelamin A processing enzyme, the zinc metalloprotease ZMPSTE24. Progeroid syndromes resulting from mutations in these genes include the clinically related disorders Hutchinson-Gilford progeria syndrome (HGPS), mandibuloacral dysplasia-type B, and restrictive dermopathy. These diseases have features that overlap with one another and with some aspects of physiological aging, including bone defects resembling osteoporosis and atherosclerosis (the latter primarily in HGPS). The progeroid syndromes have ignited keen interest in the relationship between defective prelamin A processing and its accumulation in normal physiological aging. In this review, we examine the hypothesis that diminished processing of prelamin A by ZMPSTE24 is a driver of physiological aging. We review features a new mouse () that produces solely unprocessed prelamin A and provides an ideal model for examining the effects of its accumulation during aging. We also discuss existing data on the accumulation of prelamin A or its variants in human physiological aging, which call out for further validation and more rigorous experimental approaches to determine if prelamin A contributes to normal aging.
Topics: Humans; Animals; Mice; Lamin Type A; Metalloendopeptidases; Health Promotion; Progeria; Aging; Membrane Proteins
PubMed: 37885131
DOI: 10.1080/19491034.2023.2270345