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Long lifetime and tissue-specific accumulation of lamin A/C in Hutchinson-Gilford progeria syndrome.The Journal of Cell Biology Jan 2024LMNA mutations cause laminopathies that afflict the cardiovascular system and include Hutchinson-Gilford progeria syndrome. The origins of tissue specificity in these...
LMNA mutations cause laminopathies that afflict the cardiovascular system and include Hutchinson-Gilford progeria syndrome. The origins of tissue specificity in these diseases are unclear as the lamin A/C proteins are broadly expressed. We show that LMNA transcript levels are not predictive of lamin A/C protein levels across tissues and use quantitative proteomics to discover that tissue context and disease mutation each influence lamin A/C protein's lifetime. Lamin A/C's lifetime is an order of magnitude longer in the aorta, heart, and fat, where laminopathy pathology is apparent, than in the liver and intestine, which are spared from the disease. Lamin A/C is especially insoluble in cardiovascular tissues, which may limit degradation and promote protein stability. Progerin is even more long lived than lamin A/C in the cardiovascular system and accumulates there over time. Progerin accumulation is associated with impaired turnover of hundreds of abundant proteins in progeroid tissues. These findings identify impaired lamin A/C protein turnover as a novel feature of laminopathy syndromes.
Topics: Humans; Lamin Type A; Mutation; Progeria; Proteomics
PubMed: 37966721
DOI: 10.1083/jcb.202307049 -
Experimental Cell Research Jan 2012Lamin A is a component of the nuclear envelope that is synthesized as a precursor prelamin A molecule and then processed into mature lamin A through sequential steps of... (Review)
Review
Lamin A is a component of the nuclear envelope that is synthesized as a precursor prelamin A molecule and then processed into mature lamin A through sequential steps of posttranslational modifications and proteolytic cleavages. Remarkably, over 400 distinct point mutations have been so far identified throughout the LMNA gene, which result in the development of at least ten distinct human disorders, collectively known as laminopathies, among which is the premature aging disease Hutchinson-Gilford progeria syndrome (HGPS). The majority of HGPS cases are associated with a single point mutation in the LMNA gene that causes the production of a permanently farnesylated mutant lamin A protein termed progerin. The mechanism by which progerin leads to premature aging and the classical HGPS disease phenotype as well as the relationship between this disorder and the onset of analogous symptoms during the lifespan of a normal individual are not well understood. Yet, recent studies have provided critical insights on the cellular processes that are affected by accumulation of progerin and have suggested that cellular alterations in the lamin A processing pathway leading to the accumulation of farnesylated prelamin A intermediates may play a role in the aging process in the general population. In this review we provide a short background on lamin A and its maturation pathway and discuss the current knowledge of how progerin or alterations in the prelamin A processing pathway are thought to influence cell function and contribute to human aging.
Topics: Aging; Animals; Humans; Lamin Type A; Nuclear Proteins; Prenylation; Progeria; Protein Precursors
PubMed: 21871450
DOI: 10.1016/j.yexcr.2011.08.009 -
Biochimica Et Biophysica Acta Dec 2014Aging induces myriad cellular and, ultimately, physiological changes that cause a decline in an organism's functional capabilities. Although the aging process and the... (Review)
Review
Aging induces myriad cellular and, ultimately, physiological changes that cause a decline in an organism's functional capabilities. Although the aging process and the pathways that regulate it have been extensively studied, only in the last decade have we begun to appreciate that dynamic histone methylation may contribute to this process. In this review, we discuss recent work implicating histone methylation in aging. Loss of certain histone methyltransferases and demethylases changes lifespan in invertebrates, and alterations in histone methylation in aged organisms regulate lifespan and aging phenotypes, including oxidative stress-induced hormesis in yeast, insulin signaling in Caenorhabiditis elegans and mammals, and the senescence-associated secretory phenotype in mammals. In all cases where histone methylation has been shown to impact aging and aging phenotypes, it does so by regulating transcription, suggesting that this is a major mechanism of its action in this context. Histone methylation additionally regulates or is regulated by other cellular pathways that contribute to or combat aging. Given the numerous processes that regulate aging and histone methylation, and are in turn regulated by them, the role of histone methylation in aging is almost certainly underappreciated.
Topics: Aging; Animals; DNA Methylation; Histone Methyltransferases; Histone-Lysine N-Methyltransferase; Histones; Humans; Methylation; Models, Biological; Progeria; Protein Processing, Post-Translational
PubMed: 24859460
DOI: 10.1016/j.bbagrm.2014.05.008 -
Cell Cycle (Georgetown, Tex.) 2015
Topics: Aging; Animals; Cell Proliferation; Cellular Reprogramming; Cellular Senescence; Female; Fibroblasts; Humans; Induced Pluripotent Stem Cells; Male; NF-kappa B; Progeria
PubMed: 26375309
DOI: 10.1080/15384101.2015.1093443 -
Bone Aug 2019Children with Hutchinson-Gilford progeria syndrome (HGPS), a rare premature aging disease, exhibit extraskeletal calcifications detected by radiographic analysis and on...
PURPOSE
Children with Hutchinson-Gilford progeria syndrome (HGPS), a rare premature aging disease, exhibit extraskeletal calcifications detected by radiographic analysis and on physical examination. The aim of this study was to describe the natural history and pathophysiology of these abnormal calcifications in HGPS, and to determine whether medications and/or supplements tested in clinical trials alter their development.
METHODS
Children from two successive clinical trials administering 1) lonafarnib (n = 26) and 2) lonafarnib + pravastatin + zoledronic acid (n = 37) were studied at baseline (pre-therapy), one year on therapy, and at end-of-therapy (3.3-4.3 years after the baseline visit). Calcium supplementation (oral calcium carbonate) was administered during the first year of the second trial and was subsequently discontinued. Information on calcifications was obtained from physical examinations, radiographs, and serum and urinary biochemical measures. The mineral content of two skin-derived calcifications was determined by x-ray diffraction.
RESULTS
Extraskeletal calcifications were detected radiographically in 12/39 (31%) patients at baseline. The odds of exhibiting calcifications increased with age (p = 0.045). The odds were unaffected by receipt of lonafarnib, pravastatin, and zoledronate therapies. However, administration of calcium carbonate supplementation, in conjunction with all three therapeutic agents, significantly increased the odds of developing calcifications (p = 0.009), with the odds plateauing after the supplement's discontinuation. Composition analysis of calcinosis cutis showed hydroxyapatite similar to bone. Although serum calcium, phosphorus, and parathyroid hormone (PTH) were within normal limits at baseline and on-therapy, PTH increased significantly after lonafarnib initiation (p < 0.001). Both the urinary calcium/creatinine ratio and tubular reabsorption of phosphate (TRP) were elevated at baseline in 22/39 (56%) and 31/37 (84%) evaluable patients, respectively, with no significant changes while on-therapy. The mean calcium × phosphorus product (Ca × Pi) was within normal limits, but plasma magnesium decreased over both clinical trials. Fibroblast growth factor 23 (FGF23) was lower compared to age-matched controls (p = 0.03).
CONCLUSIONS
Extraskeletal calcifications increased with age in children with HGPS and were composed of hydroxyapatite. The urinary calcium/creatinine ratio and TRP were elevated for age while FGF23 was decreased. Magnesium decreased and PTH increased after lonafarnib therapy which may alter the ability to mobilize calcium. These findings demonstrate that children with HGPS with normal renal function and an unremarkable Ca × Pi develop extraskeletal calcifications by an unidentified mechanism that may involve decreased plasma magnesium and FGF23. Calcium carbonate accelerated their development and is, therefore, not recommended for routine supplementation in these children.
Topics: Calcinosis; Calcium; Child; Child, Preschool; Creatinine; Female; Fibroblast Growth Factor-23; Humans; In Vitro Techniques; Lamin Type A; Male; Parathyroid Hormone; Piperidines; Pravastatin; Progeria; Pyridines; Zoledronic Acid
PubMed: 31077852
DOI: 10.1016/j.bone.2019.05.008 -
Histochemistry and Cell Biology Apr 2016Hutchinson-Gilford progeria syndrome (HGPS) is an extremely rare premature aging disease presenting many features resembling the normal aging process. HGPS patients die... (Review)
Review
Hutchinson-Gilford progeria syndrome (HGPS) is an extremely rare premature aging disease presenting many features resembling the normal aging process. HGPS patients die before the age of 20 years due to cardiovascular problems and heart failure. HGPS is linked to mutations in the LMNA gene encoding the intermediate filament protein lamin A. Lamin A is a major component of the nuclear lamina, a scaffold structure at the nuclear envelope that defines mechanochemical properties of the nucleus and is involved in chromatin organization and epigenetic regulation. Lamin A is also present in the nuclear interior where it fulfills lamina-independent functions in cell signaling and gene regulation. The most common LMNA mutation linked to HGPS leads to mis-splicing of the LMNA mRNA and produces a mutant lamin A protein called progerin that tightly associates with the inner nuclear membrane and affects the dynamic properties of lamins. Progerin expression impairs many important cellular processes providing insight into potential disease mechanisms. These include changes in mechanosignaling, altered chromatin organization and impaired genome stability, and changes in signaling pathways, leading to impaired regulation of adult stem cells, defective extracellular matrix production and premature cell senescence. In this review, we discuss these pathways and their potential contribution to the disease pathologies as well as therapeutic approaches used in preclinical and clinical tests.
Topics: Aging, Premature; Cell Nucleus; Cellular Senescence; Humans; Lamin Type A; Mutation; Progeria
PubMed: 26847180
DOI: 10.1007/s00418-016-1411-1 -
Deutsches Arzteblatt International Jul 2019Segmental progeroid syndromes (SPS) are rare hereditary diseases in which the affected individuals show signs of premature aging in more than one organ or type of... (Review)
Review
BACKGROUND
Segmental progeroid syndromes (SPS) are rare hereditary diseases in which the affected individuals show signs of premature aging in more than one organ or type of tissue. We review the clinical and genetic features of some of these syndromes and discuss the extent to which their study affords a complementary opportunity to study aging processes in general.
METHODS
This review is based on publications retrieved by a selective search in PubMed.
RESULTS
Segmental progeroid syndromes are a clinically and genetically heterogeneous group of hereditary diseases. They can be categorized, for example, by the age of onset of manifestations (congenital vs. infantile vs. juvenile/adult forms). They are diagnosed on clinical grounds supplemented by genetic testing on the basis of next-generation sequencing, which is of central importance in view of the marked heterogeneity and complexity of their overlapping clinical features. The elucidation of the genetic and molecular causes of these diseases can lead to causally directed treatment, as shown by the initial clinical trials in Hutchinson- Gilford progeria syndrome. The molecular features of SPS are identical in many ways to those of "physiological" aging. Thus, studying the molecular mechanisms of SPS may be helpful for the development of molecularly defined treatment approaches for age-associated diseases in general.
CONCLUSION
Segmental progeroid syndromes are a complex group of diseases with overlapping clinical features. Current research efforts focus on the elucidation of the molecular mechanisms of these diseases, most of which are very rare. This should enable the development of treatments that might be applicable to general processes of aging as well.
Topics: Aging, Premature; Clinical Trials as Topic; Humans; Progeria; Syndrome
PubMed: 31452499
DOI: 10.3238/arztebl.2019.0489 -
BMB Reports Jul 2018Lamin A and its alternative splicing product Lamin C are the key intermediate filaments (IFs) of the inner nuclear membrane intermediate filament. Lamin A/C forms the... (Review)
Review
Lamin A and its alternative splicing product Lamin C are the key intermediate filaments (IFs) of the inner nuclear membrane intermediate filament. Lamin A/C forms the inner nuclear mesh with Lamin B and works as a frame with a nuclear shape. In addition to supporting the function of nucleus, nuclear lamins perform important roles such as holding the nuclear pore complex and chromatin. However, mutations on the Lamin A or Lamin B related proteins induce various types of human genetic disorders and diseases including premature aging syndromes, muscular dystrophy, lipodystrophy and neuropathy. In this review, we briefly overview the relevance of genetic mutations of Lamin A, human disorders and laminopathies. We also discuss a mouse model for genetic diseases. Finally, we describe the current treatment for laminopathies. [BMB Reports 2018; 51(7): 327-337].
Topics: Animals; Disease Models, Animal; Enzyme Inhibitors; Humans; Lamin Type A; Lipodystrophy; Muscular Dystrophies; Mutation; Progeria
PubMed: 29764566
DOI: 10.5483/bmbrep.2018.51.7.113 -
Aging Cell Aug 2013Lamins are nuclear intermediate filaments. In addition to their structural roles, they are implicated in basic nuclear functions such as chromatin organization, DNA... (Review)
Review
Lamins are nuclear intermediate filaments. In addition to their structural roles, they are implicated in basic nuclear functions such as chromatin organization, DNA replication, transcription, DNA repair, and cell-cycle progression. Mutations in human LMNA gene cause several diseases termed laminopathies. One of the laminopathic diseases is Hutchinson-Gilford progeria syndrome (HGPS), which is caused by a spontaneous mutation and characterized by premature aging. HGPS phenotypes share certain similarities with several apparently comparable medical conditions, such as aging and atherosclerosis, with the conspicuous absence of neuronal degeneration and cancer rarity during the short lifespan of the patients. Cell lines from HGPS patients are characterized by multiple nuclear defects, which include abnormal morphology, altered histone modification patterns, and increased DNA damage. These cell lines provide insight into the molecular pathways including senescence that require lamins A and B1. Here, we review recent data on HGPS phenotypes through the lens of transcriptional deregulation caused by lack of functional lamin A, progerin accumulation, and lamin B1 silencing.
Topics: Adult Stem Cells; Cell Nucleus; Chromatin Assembly and Disassembly; DNA Repair; Gene Silencing; Humans; Lamin Type A; Lamin Type B; Mechanotransduction, Cellular; Nuclear Proteins; Phenotype; Progeria; Protein Precursors; Telomere; Transcription, Genetic
PubMed: 23496208
DOI: 10.1111/acel.12070 -
Nucleus (Austin, Tex.) 2011Hutchinson-Gilford Progeria Syndrome (HGPS) is a severe premature aging syndrome that affects children. These children display characteristics associated with normal... (Review)
Review
Hutchinson-Gilford Progeria Syndrome (HGPS) is a severe premature aging syndrome that affects children. These children display characteristics associated with normal aging and die young usually from cardiovascular problems or stroke. Classical HGPS is caused by mutations in the gene encoding the nuclear structural protein lamin A. This mutation leads to a novel version of lamin A that retains a farnesyl group from its processing. This protein is called Progerin and is toxic to cellular function. Pre-lamin A is an immature version of lamin A and also has a farnesylation modification, which is cleaved in the maturation process to create lamin A.
Topics: Biomedical Research; England; Humans; Lamin Type A; Mutation; Nuclear Proteins; Progeria; Protein Precursors; Universities
PubMed: 22064469
DOI: 10.4161/nucl.2.6.17605