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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 -
Current Problems in Cardiology Sep 2022Oxidative stress (OS) is one of the most frequently recognized causes of ageing. Telomere erosion, defects in the DNA damage response and alterations in the nuclear... (Review)
Review
Oxidative stress (OS) is one of the most frequently recognized causes of ageing. Telomere erosion, defects in the DNA damage response and alterations in the nuclear architecture are also associated with premature ageing. The most severe premature ageing syndrome, Hutchinson-Gilford progeria syndrome (HGPS) is associated with alterations in nuclear shape resulting in the deregulation of lamin A/C. In this review we describe emerging data reporting the role of OS and antioxidant defence in progeroid syndromes focusing on HGPS. We explore precise antioxidant defence mechanisms and related drugs that may create a potential path out of the woods in this disease. Pathways regulated by Nuclear factor E2 related factor (Nrf2), by Nuclear Factor kappa B (NF-kB), and related to the Unfolded Protein Response (UPR) and Endoplasmic Reticulum (ER) stress are under investigation in HGPS patients for which the goal is a significant lifespan extension in particular by postponing atherosclerosis-related complications.
Topics: Antioxidants; Cardiovascular Diseases; Cell Nucleus; Humans; Oxidative Stress; Progeria
PubMed: 34167843
DOI: 10.1016/j.cpcardiol.2021.100900 -
Biochemical Society Transactions Dec 2011Progeroid laminopathies are accelerated aging syndromes caused by defects in nuclear envelope proteins. Accordingly, mutations in the LMNA gene and functionally related... (Review)
Review
Progeroid laminopathies are accelerated aging syndromes caused by defects in nuclear envelope proteins. Accordingly, mutations in the LMNA gene and functionally related genes have been described to cause HGPS (Hutchinson-Gilford progeria syndrome), MAD (mandibuloacral dysplasia) or RD (restrictive dermopathy). Functional studies with animal and cellular models of these syndromes have facilitated the identification of the molecular alterations and regulatory pathways involved in progeria development. We have recently described a novel regulatory pathway involving miR-29 and p53 tumour suppressor which has provided valuable information on the molecular components orchestrating the response to nuclear damage stress. Furthermore, by using progeroid mice deficient in ZMPSTE24 (zinc metalloprotease STE24 homologue) involved in lamin A maturation, we have demonstrated that, besides these abnormal cellular responses to stress, dysregulation of the somatotropic axis is responsible for some of the alterations associated with progeria. Consistent with these observations, pharmacological restoration of the somatotroph axis in these mice delays the onset of their progeroid features, significantly extending their lifespan and supporting the importance of systemic alterations in progeria progression. Finally, we have very recently identified a novel progeroid syndrome with distinctive features from HGPS and MAD, which we have designated NGPS (Néstor-Guillermo progeria syndrome) (OMIM #614008). This disorder is caused by a mutation in BANF1, a gene encoding a protein with essential functions in the assembly of the nuclear envelope, further illustrating the importance of the nuclear lamina integrity for human health and providing additional support to the study of progeroid syndromes as a valuable source of information on human aging.
Topics: Animals; DNA Damage; Humans; Membrane Proteins; MicroRNAs; Progeria; Somatotrophs; Tumor Suppressor Protein p53
PubMed: 22103512
DOI: 10.1042/BST20110677 -
Clinical Radiology Jul 1976Progeria or 'prematurely old' is an autosomal recessive trait that appears insidiously at or after the age of 6 months. Two affected siblings are reported showing...
Progeria or 'prematurely old' is an autosomal recessive trait that appears insidiously at or after the age of 6 months. Two affected siblings are reported showing radiologically progressive attenuation of the clavicles and terminal phalanges, widening of cranial sutures and mandibular hypoplasia. Scleroderma was also present. Out of 59 previously published cases five had scleroderma before the age of 2 years. Only three families with affected siblings have been previously recorded.
Topics: Bone Resorption; Child, Preschool; Clavicle; Female; Fingers; Humans; Infant; Male; Mandible; Mandibular Diseases; Pedigree; Progeria; Radiography; Scleroderma, Systemic
PubMed: 975740
DOI: 10.1016/s0009-9260(76)80082-7 -
Aging Cell Sep 2023Hutchinson-Gilford progeria syndrome (HGPS) is a premature aging disorder affecting tissues of mesenchymal origin. Most individuals with HGPS harbor a de novo...
Hutchinson-Gilford progeria syndrome (HGPS) is a premature aging disorder affecting tissues of mesenchymal origin. Most individuals with HGPS harbor a de novo c.1824C > T (p.G608G) mutation in the gene encoding lamin A (LMNA), which activates a cryptic splice donor site resulting in production of the toxic "progerin" protein. Clinical manifestations include growth deficiency, lipodystrophy, sclerotic dermis, cardiovascular defects, and bone dysplasia. Here we utilized the Lmna knock-in (KI) mouse model of HGPS to further define mechanisms of bone loss associated with normal and premature aging disorders. Newborn skeletal staining of KI mice revealed altered rib cage shape and spinal curvature, and delayed calvarial mineralization with increased craniofacial and mandibular cartilage content. MicroCT analysis and mechanical testing of adult femurs indicated increased fragility associated with reduced bone mass, recapitulating the progressive bone deterioration that occurs in HGPS patients. We investigated mechanisms of bone loss in KI mice at the cellular level in bone cell populations. Formation of wild-type and KI osteoclasts from marrow-derived precursors was inhibited by KI osteoblast-conditioned media in vitro, suggesting a secreted factor(s) responsible for decreased osteoclasts on KI trabecular surfaces in vivo. Cultured KI osteoblasts exhibited abnormal differentiation characterized by reduced deposition and mineralization of extracellular matrix with increased lipid accumulation compared to wild-type, providing a mechanism for altered bone formation. Furthermore, quantitative analyses of KI transcripts confirmed upregulation of adipogenic genes both in vitro and in vivo. Thus, osteoblast phenotypic plasticity, inflammation and altered cellular cross-talk contribute to abnormal bone formation in HGPS mice.
Topics: Mice; Animals; Progeria; Aging, Premature; Mutation; Lamin Type A; Cell Differentiation; Bone Diseases, Developmental
PubMed: 37365004
DOI: 10.1111/acel.13903 -
Nature Aging Feb 2023An accumulating body of evidence indicates an association between mitotic defects and the aging process in Hutchinson-Gilford progeria syndrome (HGPS), which is a...
An accumulating body of evidence indicates an association between mitotic defects and the aging process in Hutchinson-Gilford progeria syndrome (HGPS), which is a premature aging disease caused by progerin accumulation. Here, we found that BUBR1, a core component of the spindle assembly checkpoint, was downregulated during HGPS cellular senescence. The remaining BUBR1 was anchored to the nuclear membrane by binding with the C terminus of progerin, thus further limiting the function of BUBR1. Based on this, we established a unique progerin C-terminal peptide (UPCP) that effectively blocked the binding of progerin and BUBR1 and enhanced the expression of BUBR1 by interfering with the interaction between PTBP1 and progerin. Finally, UPCP significantly inhibited HGPS cellular senescence and ameliorated progeroid phenotypes, extending the lifespan of Lmna mice. Our findings reveal an essential role for the progerin-PTBP1-BUBR1 axis in HGPS. Therapeutics designed around UPCP may be a beneficial strategy for HGPS treatment.
Topics: Mice; Animals; Progeria; Aging, Premature; Phenotype
PubMed: 37118121
DOI: 10.1038/s43587-023-00361-w -
Advances in Experimental Medicine and... 2010Autophagy is an evolutionarily conserved process essential for cellular homeostasis and organismal viability. In fact, this pathway is one of the major protein... (Review)
Review
Autophagy is an evolutionarily conserved process essential for cellular homeostasis and organismal viability. In fact, this pathway is one of the major protein degradation mechanisms in eukaryotic cells. It has been repeatedly reported that the autophagic activity of living cells decreases with age, probably contributing to the accumulation of damaged macromolecules and organelles during aging. Moreover, autophagy modulation in different model organisms has yielded very promising results suggesting that the maintenance of a proper autophagic activity contributes to extend longevity. On the other hand, recent findings have shown that distinct premature-aging murine models exhibit an extensive basal activation of autophagy instead of the characteristic decline in this process occurring during normal aging. This unexpected autophagic increase in progeroid models is usually associated with a series of metabolic alterations resembling those occurring under calorie restriction or in other situations reported to prolong life-span. In this chapter, we will discuss the current knowledge on the relationship between the autophagy pathway and aging with a special emphasis on the unexpected and novel link between premature aging and autophagy up-regulation.
Topics: Aging; Animals; Autophagy; Disease Models, Animal; Humans; Progeria; Signal Transduction
PubMed: 20886757
DOI: 10.1007/978-1-4419-7002-2_6 -
American Journal of Ophthalmology Oct 2017To establish the natural history of ophthalmic characteristics in Progeria patients and to determine incidence of ocular manifestations.
PURPOSE
To establish the natural history of ophthalmic characteristics in Progeria patients and to determine incidence of ocular manifestations.
DESIGN
Retrospective case series of patients with Progeria who were seen between 2007 and 2016.
METHODS
Setting: Tertiary-care academic center.
PATIENT POPULATION
Fourteen patients (28 eyes) with Hutchinson-Gilford Progeria syndrome were included for statistical analysis from a total of 84 patients who have been enrolled in clinical trials for Progeria at Boston Children's Hospital. Clinical treatment trial patients who were not seen at the Department of Ophthalmology at our hospital, but for whom we had detailed clinical ophthalmologic records, were also included. This essentially represents an estimated 20% of the world's known patients with Progeria. Interventions or Observation Procedures: Complete ophthalmic examination.
MAIN OUTCOME MEASURES
Visual acuity, stereoacuity, refraction, clinical findings of slit-lamp and dilated fundus examinations.
RESULTS
Ophthalmic manifestations noted were hyperopia and signs of ocular surface disease owing to nocturnal lagophthalmos and exposure keratopathy. Additional ophthalmic manifestations included reduced brow hair, madarosis, and reduced accommodation. Most patients had relatively good acuity; however, advanced ophthalmic disease was associated with reduced acuity.
CONCLUSIONS
Children with Progeria are at risk for serious ophthalmic complications owing to ocular surface disease. Children with Progeria should have an ophthalmic evaluation at the time of diagnosis and at least yearly after that. Aggressive ocular surface lubrication is recommended, including the use of tape tarsorrhaphy at night.
Topics: Adolescent; Child; Child, Preschool; Corneal Diseases; Eye Diseases; Eyebrows; Eyeglasses; Eyelid Diseases; Female; Follow-Up Studies; Humans; Male; Progeria; Refraction, Ocular; Retrospective Studies; Visual Acuity
PubMed: 28756152
DOI: 10.1016/j.ajo.2017.07.020 -
Pediatric Dermatology 2015Hutchinson-Gilford progeria syndrome is a rare genetic disorder characterized by premature aging of the skin, bones, heart, and blood vessels. We report a 6-year-old boy... (Review)
Review
Hutchinson-Gilford progeria syndrome is a rare genetic disorder characterized by premature aging of the skin, bones, heart, and blood vessels. We report a 6-year-old boy who was born at full term but presented with scleroderma-like appearance at 1 month of age and gradually developed clinical manifestations of progeria. He had characteristic facial features of prominent eyes, scalp, and leg veins; loss of scalp hair, eyebrows, and eyelashes; stunted growth; scleroderma-like changes of the skin; and a premature aged appearance. Metabolic investigations showed transient methylmalonic aciduria, and genetic testing of the peripheral blood identified the c.1824C>T heterozygous LMNA mutation. The present case is reported because of its rarity.
Topics: Child; Gene Expression Regulation; Genetic Predisposition to Disease; Humans; Lamin Type A; Male; Mutation; Progeria; Rare Diseases
PubMed: 25556323
DOI: 10.1111/pde.12406 -
ELife Mar 2023Clinical trials have demonstrated that lonafarnib, a farnesyltransferase inhibitor, extends the lifespan in patients afflicted by Hutchinson-Gilford progeria syndrome, a...
Clinical trials have demonstrated that lonafarnib, a farnesyltransferase inhibitor, extends the lifespan in patients afflicted by Hutchinson-Gilford progeria syndrome, a devastating condition that accelerates many characteristics of aging and results in premature death due to cardiovascular sequelae. The US Food and Drug Administration approved Zokinvy (lonafarnib) in November 2020 for treating these patients, yet a detailed examination of drug-associated effects on cardiovascular structure, properties, and function has remained wanting. In this paper, we report encouraging outcomes of daily post-weaning treatment with lonafarnib on the composition and biomechanical phenotype of elastic and muscular arteries as well as associated cardiac function in a well-accepted mouse model of progeria that exhibits severe perimorbid cardiovascular disease. Lonafarnib resulted in 100% survival of the treated progeria mice to the study end-point (time of 50% survival of untreated mice), with associated improvements in arterial structure and function working together to significantly reduce pulse wave velocity and improve left ventricular diastolic function. By contrast, neither treatment with the mTOR inhibitor rapamycin alone nor dual treatment with lonafarnib plus rapamycin improved outcomes over that achieved with lonafarnib monotherapy.
Topics: Mice; Animals; Progeria; Pulse Wave Analysis; Piperidines; Sirolimus; Lamin Type A
PubMed: 36930696
DOI: 10.7554/eLife.82728