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

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.

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Towards a Drosophila model of Hutchinson–Gilford progeria syndrome

Biochemical Society Transactions ◽

10.1042/bst0361389 ◽

2008 ◽

Vol 36 (6) ◽

pp. 1389-1392 ◽

Cited By ~ 6

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.

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

Science Translational Medicine ◽

10.1126/scitranslmed.abd2655 ◽

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.

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Linking ABCC6 Deficiency in Primary Human Dermal Fibroblasts of PXE Patients to p21-Mediated Premature Cellular Senescence and the Development of a Proinflammatory Secretory Phenotype

International Journal of Molecular Sciences ◽

10.3390/ijms21249665 ◽

2020 ◽

Vol 21 (24) ◽

pp. 9665

Author(s):

Janina Tiemann ◽

Thomas Wagner ◽

Christopher Lindenkamp ◽

Ricarda Plümers ◽

Isabel Faust ◽

...

Keyword(s):

Gene Expression ◽

Cellular Senescence ◽

Kinase Inhibitor ◽

Dermal Fibroblasts ◽

Cellular Aging ◽

Premature Aging ◽

Molecular Characteristics ◽

Human Dermal Fibroblasts ◽

Monocyte Chemoattractant Protein 1 ◽

Secretory Phenotype

Pseudoxanthoma elasticum (PXE) is a rare autosomal-recessive disorder that is mainly caused by mutations in the ATP-binding cassette sub-family C member 6 (ABCC6) gene. Clinically PXE is characterized by a loss of skin elasticity, arteriosclerosis or visual impairments. It also shares some molecular characteristics with known premature aging syndromes like the Hutchinson–Gilford progeria syndrome (HGPS). However, little is known about accelerated aging processes, especially on a cellular level for PXE now. Therefore, this study was performed to reveal a potential connection between premature cellular aging and PXE pathogenesis by analyzing cellular senescence, a corresponding secretory phenotype and relevant factors of the cell cycle control in primary human dermal fibroblasts of PXE patients. Here, we could show an increased senescence-associated β-galactosidase (SA-β-Gal) activity as well as an increased expression of proinflammatory factors of a senescence-associated secretory phenotype (SASP) like interleukin 6 (IL6) and monocyte chemoattractant protein-1 (MCP1). We further observed an increased gene expression of the cyclin-dependent kinase inhibitor (CDKI) p21, but no simultaneous induction of p53 gene expression. These data indicate that PXE is associated with premature cellular senescence, which is possibly triggered by a p53-independent p21-mediated mechanism leading to a proinflammatory secretory phenotype.

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Hutchinson–Gilford Progeria Syndrome (Hgps) And Application Of Gene Therapy Based Crispr/Cas Technology As A Promising Innovative Treatment Approach

Recent Patents on Biotechnology ◽

10.2174/1872208315666210928114720 ◽

2021 ◽

Vol 15 ◽

Author(s):

Mekha Rajeev ◽

Chameli Ratan ◽

Karthik Krishnan ◽

Meenu Vijayan

Keyword(s):

De Novo ◽

Treatment Approach ◽

Genetic Disorder ◽

Symptomatic Relief ◽

Dominant Negative ◽

Premature Aging ◽

Lamin A ◽

Promising Therapeutic Approach ◽

Progeria Syndrome ◽

Hutchinson Gilford Progeria Syndrome

Background: Hutchinson–Gilford progeria syndrome (HGPS) also known as progeria of childhood or progeria is a rare, rapid, autosomal dominant genetic disorder characterized by premature aging which occurs shortly after birth. HGPS occurs as a result of de novo point mutation in the gene recognized as LMNA gene that encodes two proteins Lamin A protein and Lamin C protein which are the structural components of the nuclear envelope. Mutations in the gene trigger abnormal splicing and induce internal deletion of 50 amino acids leading to the development of a truncated form of Lamin A protein known as Progerin. Progerin generation can be considered as the crucial step in HGPS since the protein is highly toxic to human cells, permanently farnesylated, and exhibits variation in several biochemical and structural properties within the individual. HGPS also produces complications such as skin alterations, growth failure, atherosclerosis, hair and fat loss, and bone and joint diseases. We have also revised all relevant patents relating to Hutchinson-gilford progeria syndrome and its therapy in the current article. Method: The goal of the present review article is to provide information about Hutchinson–Gilford progeria syndrome (HGPS) and the use of CRISPR/Cas technology as a promising treatment approach in the treatment of the disease. The review also discusses about different pharmacological and non-pharmacological methods of treatment currently used for HGPS. Results : The main limitation associated with progeria is the lack of a definitive cure. The existing treatment modality provides only symptomatic relief. Therefore, it is high time to develop a therapeutic method that hastens premature aging in such patients. Conclusion: CRISPR/Cas technology is a novel gene-editing tool that allows genome editing at specific loci, and is found to be a promising therapeutic approach for the treatment of genetic disorders such as HGPS where dominant-negative mutations take place.

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Emerging candidate treatment strategies for Hutchinson-Gilford progeria syndrome

Biochemical Society Transactions ◽

10.1042/bst20170141 ◽

2017 ◽

Vol 45 (6) ◽

pp. 1279-1293 ◽

Cited By ~ 6

Author(s):

Charlotte Strandgren ◽

Gwladys Revêchon ◽

Agustín Sola Carvajal ◽

Maria Eriksson

Keyword(s):

De Novo ◽

Disease Incidence ◽

Treatment Strategies ◽

Premature Aging ◽

Lamin A ◽

Lmna Gene ◽

Progeria Syndrome ◽

Hutchinson Gilford Progeria Syndrome

Hutchinson-Gilford progeria syndrome (HGPS, progeria) is an extremely rare premature aging disorder affecting children, with a disease incidence of ∼1 in 18 million individuals. HGPS is usually caused by a de novo point mutation in exon 11 of the LMNA gene (c.1824C>T, p.G608G), resulting in the increased usage of a cryptic splice site and production of a truncated unprocessed lamin A protein named progerin. Since the genetic cause for HGPS was published in 2003, numerous potential treatment options have rapidly emerged. Strategies to interfere with the post-translational processing of lamin A, to enhance progerin clearance, or directly target the HGPS mutation to reduce the progerin-producing alternative splicing of the LMNA gene have been developed. Here, we give an up-to-date resume of the contributions made by our and other research groups to the growing list of different candidate treatment strategies that have been tested, both in vitro, in vivo in mouse models for HGPS and in clinical trials in HGPS patients.

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

Nature Communications ◽

10.1038/s41467-019-13018-3 ◽

2019 ◽

Vol 10 (1) ◽

Cited By ~ 20

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.

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Nuclear stiffening and chromatin softening with progerin expression leads to an attenuated nuclear response to force

Soft Matter ◽

10.1039/c5sm00521c ◽

2015 ◽

Vol 11 (32) ◽

pp. 6412-6418 ◽

Cited By ~ 26

Author(s):

Elizabeth A. Booth ◽

Stephen T. Spagnol ◽

Turi A. Alcoser ◽

Kris Noel Dahl

Keyword(s):

Nuclear Structure ◽

Nuclear Protein ◽

Premature Aging ◽

Lamin A ◽

Mutant Form ◽

Progeria Syndrome ◽

Hutchinson Gilford Progeria Syndrome ◽

Nuclear Response

Progerin, a mutant form of the nuclear protein lamin A, is associated with the premature aging disorder Hutchinson-Gilford progeria syndrome. Progerin expression leads to a variety of changes in nuclear structure, mechanics and mechano-responsiveness.

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Importance of molecular cell biology investigations in human medicine in the story of the Hutchinson-Gilford progeria syndrome

Interdisciplinary Toxicology ◽

10.2478/v10102-010-0018-y ◽

2010 ◽

Vol 3 (3) ◽

pp. 89-93 ◽

Cited By ~ 1

Author(s):

Ivan Raška

Keyword(s):

Cell Biology ◽

Basic Mechanism ◽

Human Medicine ◽

Premature Aging ◽

Lamin A ◽

Nucleotide Position ◽

Molecular Cell Biology ◽

Progeria Syndrome ◽

Hutchinson Gilford Progeria Syndrome ◽

Precursor Mrna

Importance of molecular cell biology investigations in human medicine in the story of the Hutchinson-Gilford progeria syndromeRanged among laminopathies, Hutchinson-Gilford progeria syndrome is a syndrome that involves premature aging, leading usually to death at the age between 10 to 14 years predominatly due to a myocardial infarction or a stroke. In the lecture I shall overview the importance of molecular cell biology investigations that led to the discovery of the basic mechanism standing behind this rare syndrome. The genetic basis in most cases is a mutation at the nucleotide position 1824 of the lamin A gene. At this position, cytosine is substituted for thymine so that a cryptic splice site within the precursor mRNA for lamin A is generated. This results in a production of abnormal lamin A, termed progerin, its presence in cells having a deleterious dominant effect. Depending on the cell type and tissue, progerin induces a pleiotropy of defects that vary in different tissues. The present endeavour how to challenge this terrible disease will be also mentioned.

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DNA-damage accumulation and replicative arrest in Hutchinson–Gilford progeria syndrome

Biochemical Society Transactions ◽

10.1042/bst20110687 ◽

2011 ◽

Vol 39 (6) ◽

pp. 1764-1769 ◽

Cited By ~ 46

Author(s):

Phillip R. Musich ◽

Yue Zou

Keyword(s):

Dna Damage ◽

Cell Cycle Progression ◽

Severe Form ◽

Premature Aging ◽

Lamin A ◽

Repair System ◽

Group A ◽

Fork Stalling ◽

Progeria Syndrome ◽

Hutchinson Gilford Progeria Syndrome

A common feature of progeria syndromes is a premature aging phenotype and an enhanced accumulation of DNA damage arising from a compromised repair system. HGPS (Hutchinson–Gilford progeria syndrome) is a severe form of progeria in which patients accumulate progerin, a mutant lamin A protein derived from a splicing variant of the lamin A/C gene (LMNA). Progerin causes chromatin perturbations which result in the formation of DSBs (double-strand breaks) and abnormal DDR (DNA-damage response). In the present article, we review recent findings which resolve some mechanistic details of how progerin may disrupt DDR pathways in HGPS cells. We propose that progerin accumulation results in disruption of functions of some replication and repair factors, causing the mislocalization of XPA (xeroderma pigmentosum group A) protein to the replication forks, replication fork stalling and, subsequently, DNA DSBs. The binding of XPA to the stalled forks excludes normal binding by repair proteins, leading to DSB accumulation, which activates ATM (ataxia telangiectasia mutated) and ATR (ATM- and Rad3-related) checkpoints, and arresting cell-cycle progression.

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

Cells ◽

10.3390/cells10071598 ◽

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.

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