scholarly journals Impact of Progerin Expression on Adipogenesis in Hutchinson—Gilford Progeria Skin-Derived Precursor Cells

Cells ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1598
Author(s):  
Farah Najdi ◽  
Peter Krüger ◽  
Karima Djabali
Keyword(s):  
Cellular Senescence ◽  
Adipogenic Differentiation ◽  
Subcutaneous Fat ◽  
Premature Aging ◽  
Normal Fibroblast ◽  
Potential Treatment ◽  
Differentiation Potential ◽  
Prelamin A ◽  
Progeria Syndrome ◽  
Hutchinson Gilford Progeria Syndrome

Hutchinson–Gilford progeria syndrome (HGPS) is a segmental premature aging disease caused by a mutation in LMNA. The mutation generates a truncated and farnesylated form of prelamin A, called progerin. Affected individuals develop several features of normal aging, including lipodystrophy caused by the loss of general subcutaneous fat. To determine whether premature cellular senescence is responsible for the altered adipogenesis in patients with HGPS, we evaluated the differentiation of HGPS skin-derived precursor stem cells (SKPs) into adipocytes. The SKPs were isolated from primary human HGPS and normal fibroblast cultures, with senescence of 5 and 30%. We observed that the presence of high numbers of senescent cells reduced SKPs’ adipogenic differentiation potential. Treatment with baricitinib, a JAK–STAT inhibitor, ameliorated the ability of HGPS SKPs to differentiate into adipocytes. Our findings suggest that the development of lipodystrophy in patients with HGPS may be associated with an increased rate of cellular senescence and chronic inflammation.

A genome-wide CRISPR-based screen identifies KAT7 as a driver of cellular senescence

2021 ◽  
Vol 13 (575) ◽  
pp. eabd2655
Author(s):  
Wei Wang ◽  
Yuxuan Zheng ◽  
Shuhui Sun ◽  
Wei Li ◽  
Moshi Song ◽  
...  
Keyword(s):  
Cellular Senescence ◽  
Werner Syndrome ◽  
Embryonic Stem ◽  
Accelerated Aging ◽  
Premature Aging ◽  
Mesenchymal Precursor Cells ◽  
Genome Wide ◽  
A Genome ◽  
Progeria Syndrome ◽  
Hutchinson Gilford Progeria Syndrome

Understanding the genetic and epigenetic bases of cellular senescence is instrumental in developing interventions to slow aging. We performed genome-wide CRISPR-Cas9–based screens using two types of human mesenchymal precursor cells (hMPCs) exhibiting accelerated senescence. The hMPCs were derived from human embryonic stem cells carrying the pathogenic mutations that cause the accelerated aging diseases Werner syndrome and Hutchinson-Gilford progeria syndrome. Genes whose deficiency alleviated cellular senescence were identified, including KAT7, a histone acetyltransferase, which ranked as a top hit in both progeroid hMPC models. Inactivation of KAT7 decreased histone H3 lysine 14 acetylation, repressed p15INK4b transcription, and alleviated hMPC senescence. Moreover, lentiviral vectors encoding Cas9/sg-Kat7, given intravenously, alleviated hepatocyte senescence and liver aging and extended life span in physiologically aged mice as well as progeroid Zmpste24−/− mice that exhibit a premature aging phenotype. CRISPR-Cas9–based genetic screening is a robust method for systematically uncovering senescence genes such as KAT7, which may represent a therapeutic target for developing aging interventions.

scholarly journals Neuropeptide Y Enhances Progerin Clearance and Ameliorates the Senescent Phenotype of Human Hutchinson-Gilford Progeria Syndrome Cells

2020 ◽  
Vol 75 (6) ◽  
pp. 1073-1078 ◽  
Author(s):  
Célia A Aveleira ◽  
Marisa Ferreira-Marques ◽  
Luísa Cortes ◽  
Jorge Valero ◽  
Dina Pereira ◽  
...  
Keyword(s):  
Neuropeptide Y ◽  
Caloric Restriction ◽  
Cellular Senescence ◽  
Dermal Fibroblasts ◽  
Cellular Aging ◽  
Premature Aging ◽  
Whole Body ◽  
Lamin A ◽  
Progeria Syndrome ◽  
Hutchinson Gilford Progeria Syndrome

Abstract Hutchinson-Gilford progeria syndrome (HGPS, or classical progeria) is a rare genetic disorder, characterized by premature aging, and caused by a de novo point mutation (C608G) within the lamin A/C gene (LMNA), producing an abnormal lamin A protein, termed progerin. Accumulation of progerin causes nuclear abnormalities and cell cycle arrest ultimately leading to cellular senescence. Autophagy impairment is a hallmark of cellular aging, and the rescue of this proteostasis mechanism delays aging progression in HGPS cells. We have previously shown that the endogenous Neuropeptide Y (NPY) increases autophagy in hypothalamus, a brain area already identified as a central regulator of whole-body aging. We also showed that NPY mediates caloric restriction-induced autophagy. These results are in accordance with other studies suggesting that NPY may act as a caloric restriction mimetic and plays a role as a lifespan and aging regulator. The aim of the present study was, therefore, to investigate if NPY could delay HGPS premature aging phenotype. Herein, we report that NPY increases autophagic flux and progerin clearance in primary cultures of human dermal fibroblasts from HGPS patients. NPY also rescues nuclear morphology and decreases the number of dysmorphic nuclei, a hallmark of HGPS cells. In addition, NPY decreases other hallmarks of aging as DNA damage and cellular senescence. Altogether, these results show that NPY rescues several hallmarks of cellular aging in HGPS cells, suggesting that NPY can be considered a promising strategy to delay or block the premature aging of HGPS.

scholarly journals Inhibition of DNA damage response at telomeres improves the detrimental phenotypes of Hutchinson–Gilford Progeria Syndrome

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Julio Aguado ◽  
Agustin Sola-Carvajal ◽  
Valeria Cancila ◽  
Gwladys Revêchon ◽  
Peh Fern Ong ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Cellular Senescence ◽  
Genetic Disorder ◽  
Premature Aging ◽  
Telomere Dysfunction ◽  
Damage Response ◽  
Progeria Syndrome ◽  
Hutchinson Gilford Progeria Syndrome

AbstractHutchinson–Gilford progeria syndrome (HGPS) is a genetic disorder characterized by premature aging features. Cells from HGPS patients express progerin, a truncated form of Lamin A, which perturbs cellular homeostasis leading to nuclear shape alterations, genome instability, heterochromatin loss, telomere dysfunction and premature entry into cellular senescence. Recently, we reported that telomere dysfunction induces the transcription of telomeric non-coding RNAs (tncRNAs) which control the DNA damage response (DDR) at dysfunctional telomeres. Here we show that progerin-induced telomere dysfunction induces the transcription of tncRNAs. Their functional inhibition by sequence-specific telomeric antisense oligonucleotides (tASOs) prevents full DDR activation and premature cellular senescence in various HGPS cell systems, including HGPS patient fibroblasts. We also show in vivo that tASO treatment significantly enhances skin homeostasis and lifespan in a transgenic HGPS mouse model. In summary, our results demonstrate an important role for telomeric DDR activation in HGPS progeroid detrimental phenotypes in vitro and in vivo.

scholarly journals Defining substrate requirements for cleavage of farnesylated prelamin A by the integral membrane zinc metalloprotease ZMPSTE24

PLoS ONE ◽  
2020 ◽  
Vol 15 (12) ◽  
pp. e0239269
Author(s):  
Kaitlin M. Wood ◽  
Eric D. Spear ◽  
Otto W. Mossberg ◽  
Kamsi O. Odinammadu ◽  
Wenxin Xu ◽  
...  
Keyword(s):  
Cleavage Site ◽  
Mammalian Cells ◽  
Terminal Region ◽  
Proteolytic Processing ◽  
Premature Aging ◽  
Prelamin A ◽  
Zinc Metalloprotease ◽  
Progeria Syndrome ◽  
Hutchinson Gilford Progeria Syndrome

The integral membrane zinc metalloprotease ZMPSTE24 plays a key role in the proteolytic processing of farnesylated prelamin A, the precursor of the nuclear scaffold protein lamin A. Failure of this processing step results in the accumulation of permanently farnesylated forms of prelamin A which cause the premature aging disease Hutchinson-Gilford Progeria Syndrome (HGPS), as well as related progeroid disorders, and may also play a role in physiological aging. ZMPSTE24 is an intriguing and unusual protease because its active site is located inside of a closed intramembrane chamber formed by seven transmembrane spans with side portals in the chamber permitting substrate entry. The specific features of prelamin A that make it the sole known substrate for ZMPSTE24 in mammalian cells are not well-defined. At the outset of this work it was known that farnesylation is essential for prelamin A cleavage in vivo and that the C-terminal region of prelamin A (41 amino acids) is sufficient for recognition and processing. Here we investigated additional features of prelamin A that are required for cleavage by ZMPSTE24 using a well-established humanized yeast system. We analyzed the 14-residue C-terminal region of prelamin A that lies between the ZMPSTE24 cleavage site and the farnesylated cysteine, as well 23-residue region N-terminal to the cleavage site, by generating a series of alanine substitutions, alanine additions, and deletions in prelamin A. Surprisingly, we found that there is considerable flexibility in specific requirements for the length and composition of these regions. We discuss how this flexibility can be reconciled with ZMPSTE24’s selectivity for prelamin A.

scholarly journals Defining Substrate Requirements for Cleavage of Farnesylated Prelamin A by the Integral Membrane Zinc Metalloprotease ZMPSTE24

2020 ◽  
Author(s):  
Kaitlin M. Wood ◽  
Eric D. Spear ◽  
Otto W. Mossberg ◽  
Kamsi O. Odinammadu ◽  
Wenxin Xu ◽  
...  
Keyword(s):  
Cleavage Site ◽  
Mammalian Cells ◽  
Terminal Region ◽  
Proteolytic Processing ◽  
Premature Aging ◽  
Prelamin A ◽  
Zinc Metalloprotease ◽  
Progeria Syndrome ◽  
Hutchinson Gilford Progeria Syndrome

AbstractThe integral membrane zinc metalloprotease ZMPSTE24 plays a key role in the proteolytic processing of farnesylated prelamin A, the precursor of the nuclear scaffold protein lamin A. Failure of this processing step results in the accumulation of permanently farnesylated forms of prelamin A which cause the premature aging disease Hutchinson-Gilford Progeria Syndrome (HGPS), as well as related progeroid disorders, and may also play a role in physiological aging. ZMPSTE24 is an intriguing and unusual protease because its active site is located inside of a closed intramembrane chamber formed by seven transmembrane spans with side portals in the chamber permitting substrate entry. The specific features of prelamin A that make it the sole known substrate for ZMPSTE24 in mammalian cells are not well-defined. At the outset of this work it was known that farnesylation is essential for prelamin A cleavage in vivo and that the C-terminal region of prelamin A (41 amino acids) is sufficient for recognition and processing. Here we investigated additional features of prelamin A that are required for cleavage by ZMPSTE24 using a well-established humanized yeast system. We analyzed the 14-residue C-terminal region of prelamin A that lies between the ZMPSTE24 cleavage site and the farnesylated cysteine, as well 23-residue region N-terminal to the cleavage site, by generating a series of alanine substitutions, alanine additions, and deletions in prelamin A. Surprisingly, we found that there is considerable flexibility in specific requirements for the length and composition of these regions. We discuss how this flexibility can be reconciled with ZMPSTE24’s selectivity for prelamin A.

scholarly journals Activating the synthesis of progerin, the mutant prelamin A in Hutchinson–Gilford progeria syndrome, with antisense oligonucleotides

2009 ◽  
Vol 18 (13) ◽  
pp. 2462-2471 ◽  
Author(s):  
Loren G. Fong ◽  
Timothy A. Vickers ◽  
Emily A. Farber ◽  
Christine Choi ◽  
Ui Jeong Yun ◽  
...  
Keyword(s):  
Antisense Oligonucleotides ◽  
Prelamin A ◽  
Progeria Syndrome ◽  
Hutchinson Gilford Progeria Syndrome

Towards a Drosophila model of Hutchinson–Gilford progeria syndrome

2008 ◽  
Vol 36 (6) ◽  
pp. 1389-1392 ◽  
Author(s):  
Gemma S. Beard ◽  
Joanna M. Bridger ◽  
Ian R. Kill ◽  
David R.P. Tree
Keyword(s):  
Drosophila Melanogaster ◽  
Premature Aging ◽  
Lamin A ◽  
Wild Type ◽  
Drosophila Model ◽  
Numerous Cell ◽  
Cellular Abnormalities ◽  
Progeria Syndrome ◽  
Hutchinson Gilford Progeria Syndrome ◽  
Adult Drosophila

The laminopathy Hutchinson–Gilford progeria syndrome (HGPS) is caused by the mutant lamin A protein progerin and leads to premature aging of affected children. Despite numerous cell biological and biochemical insights into the basis for the cellular abnormalities seen in HGPS, the mechanism linking progerin to the organismal phenotype is not fully understood. To begin to address the mechanism behind HGPS using Drosophila melanogaster, we have ectopically expressed progerin and lamin A. We found that ectopic progerin and lamin A phenocopy several effects of laminopathies in developing and adult Drosophila, but that progerin causes a stronger phenotype than wild-type lamin A.

scholarly journals A Very Rare Case of Coronary Artery Bypass Grafting in a Progeria Child

2019 ◽  
Vol 11 (4) ◽  
pp. NP244-NP246
Author(s):  
Rui Pedro Soares Cerejo ◽  
Rui A. N. Rodrigues ◽  
José D. Martins ◽  
Carolina G. E. C. Torres ◽  
Lídia M. Sousa ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Coronary Artery ◽  
Genetic Disorder ◽  
Artery Bypass ◽  
Early Death ◽  
Premature Aging ◽  
Artery Disease ◽  
Progeria Syndrome ◽  
Hutchinson Gilford Progeria Syndrome ◽  
Vessel Coronary Artery

Hutchinson-Gilford progeria syndrome is a rare genetic disorder, characterized by progressive premature aging and early death in the first or second decade of life, usually secondary to cardiovascular events (myocardial infarction and stroke). We report a case of a 14-year-old boy with progeria syndrome and cardiac arrest due to myocardial infarction, who was submitted to an immediate coronary angiography which revealed left main stem and three-vessel coronary artery disease. A prompt double bypass coronary artery grafting surgery was performed, and, despite successful coronary reperfusion, the patient remained in coma and brain death was declared on fourth day after surgery.

scholarly journals Hutchinson-Gilford Progeria Syndrome: A Rare Genetic Disorder

2013 ◽  
Vol 2013 ◽  
pp. 1-4
Author(s):  
Rajat G. Panigrahi ◽  
Antarmayee Panigrahi ◽  
Poornima Vijayakumar ◽  
Priyadarshini Choudhury ◽  
Sanat K. Bhuyan ◽  
...  
Keyword(s):  
Genetic Disorder ◽  
Premature Aging ◽  
Pectus Carinatum ◽  
Genetic Syndrome ◽  
Live Births ◽  
Follow Up Study ◽  
First Case ◽  
Progeria Syndrome ◽  
Hutchinson Gilford Progeria Syndrome

Hutchinson-Gilford progeria syndrome (HGPS) is a rare pediatric genetic syndrome with incidence of one per eight million live births. The disorder is characterised by premature aging, generally leading to death at approximately 13.4 years of age. This is a follow-up study of a 9-year-old male with clinical and radiographic features highly suggestive of HGPS and presented here with description of differential diagnosis and dental consideration. This is the first case report of HGPS which showed pectus carinatum structure of chest.

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