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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 -
Bone Oct 2021The nuclear envelope and nucleoskeleton are emerging as signaling centers that regulate how physical information from the extracellular matrix is biochemically... (Review)
Review
The nuclear envelope and nucleoskeleton are emerging as signaling centers that regulate how physical information from the extracellular matrix is biochemically transduced into the nucleus, affecting chromatin and controlling cell function. Bone is a mechanically driven tissue that relies on physical information to maintain its physiological function and structure. Disorder that present with musculoskeletal and cardiac symptoms, such as Emery-Dreifuss muscular dystrophies and progeria, correlate with mutations in nuclear envelope proteins including Linker of Nucleoskeleton and Cytoskeleton (LINC) complex, Lamin A/C, and emerin. However, the role of nuclear envelope mechanobiology on bone function remains underexplored. The mesenchymal stem cell (MSC) model is perhaps the most studied relationship between bone regulation and nuclear envelope function. MSCs maintain the musculoskeletal system by differentiating into multiple cell types including osteocytes and adipocytes, thus supporting the bone's ability to respond to mechanical challenge. In this review, we will focus on how MSC function is regulated by mechanical challenges both in vitro and in vivo within the context of bone function specifically focusing on integrin, β-catenin and YAP/TAZ signaling. The importance of the nuclear envelope will be explored within the context of musculoskeletal diseases related to nuclear envelope protein mutations and nuclear envelope regulation of signaling pathways relevant to bone mechanobiology in vitro and in vivo.
Topics: Biophysics; Cell Nucleus; Cytoskeleton; Humans; Muscular Dystrophy, Emery-Dreifuss; Nuclear Envelope
PubMed: 34051417
DOI: 10.1016/j.bone.2021.116023 -
Molecular Medicine (Cambridge, Mass.) Jul 2023The telomerase RNA component (TERC) gene plays an important role in telomerase-dependent extension and maintenance of the telomeres. In the event of TERC... (Review)
Review
The telomerase RNA component (TERC) gene plays an important role in telomerase-dependent extension and maintenance of the telomeres. In the event of TERC haploinsufficiency, telomere length is often affected; this, in turn, can result in the development of progeria-related diseases such as aplastic anemia (AA) and congenital keratosis. Cell reprogramming can reverse the differentiation process and can, therefore, transform cells into pluripotent stem cells with stronger differentiation and self-renewal abilities; further, cell reprograming can also extend the telomere length of these cells, which may be crucial in the diagnosis and treatment of telomere depletion diseases such as AA. In this study, we summarized the effects of TERC haploid cell reprogramming on telomere length and the correlation between this alteration and the pathogenesis of AA; by investigating the role of cell reprogramming in AA, we aimed to identify novel diagnostic indicators and therapeutic strategies for patients with AA.
Topics: Humans; Telomerase; Anemia, Aplastic; Cellular Reprogramming; Haploidy
PubMed: 37424004
DOI: 10.1186/s10020-023-00691-w -
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 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 -
Cells Sep 2023Hutchinson-Gilford progeria syndrome (HGPS) is an extremely rare genetic disorder caused by the mutant protein progerin, which is expressed by the abnormal splicing of... (Review)
Review
Hutchinson-Gilford progeria syndrome (HGPS) is an extremely rare genetic disorder caused by the mutant protein progerin, which is expressed by the abnormal splicing of the gene. HGPS affects systemic levels, with the exception of cognition or brain development, in children, showing that cellular aging can occur in the short term. Studying progeria could be useful in unraveling the causes of human aging (as well as fatal age-related disorders). Elucidating the clear cause of HGPS or the development of a therapeutic medicine could improve the quality of life and extend the survival of patients. This review aimed to (i) briefly describe how progerin was discovered as the causative agent of HGPS, (ii) elucidate the puzzling observation of the absence of primary neurological disease in HGPS, (iii) present several studies showing the deleterious effects of progerin and the beneficial effects of its inhibition, and (iv) summarize research to develop a therapy for HGPS and introduce clinical trials for its treatment.
Topics: Child; Humans; Lamin Type A; Progeria; Quality of Life; Medicine; Aging; Rare Diseases
PubMed: 37759521
DOI: 10.3390/cells12182299