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 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.

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

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.

Emerging candidate treatment strategies for Hutchinson-Gilford progeria syndrome

2017 ◽  
Vol 45 (6) ◽  
pp. 1279-1293 ◽  
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.

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

Soft Matter ◽  
2015 ◽  
Vol 11 (32) ◽  
pp. 6412-6418 ◽  
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.

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

2010 ◽  
Vol 3 (3) ◽  
pp. 89-93 ◽  
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.

scholarly journals Arterial stiffness and cardiac dysfunction in Hutchinson–Gilford Progeria Syndrome corrected by inhibition of lysyl oxidase

2021 ◽  
Vol 4 (5) ◽  
pp. e202000997
Author(s):  
Ryan von Kleeck ◽  
Emilia Roberts ◽  
Paola Castagnino ◽  
Kyle Bruun ◽  
Sonja A Brankovic ◽  
...  
Keyword(s):  
Cardiac Dysfunction ◽  
Carotid Arteries ◽  
Lysyl Oxidase ◽  
Premature Aging ◽  
Wild Type ◽  
Arterial Stiffening ◽  
Genome Wide ◽  
Mechanistic Analysis ◽  
Progeria Syndrome ◽  
Hutchinson Gilford Progeria Syndrome

Arterial stiffening and cardiac dysfunction are hallmarks of premature aging in Hutchinson–Gilford Progeria Syndrome (HGPS), but the molecular regulators remain unknown. Here, we show that the LaminAG609G mouse model of HGPS recapitulates the premature arterial stiffening and early diastolic dysfunction seen in human HGPS. Lysyl oxidase (LOX) is up-regulated in the arteries of these mice, and treatment with the LOX inhibitor, β-aminopropionitrile, improves arterial mechanics and cardiac function. Genome-wide and mechanistic analysis revealed reduced expression of the LOX-regulator, miR-145, in HGPS arteries, and forced expression of miR-145 restores normal LOX gene expression in HGPS smooth muscle cells. LOX abundance is also increased in the carotid arteries of aged wild-type mice, but its spatial expression differs from HGPS and its up-regulation is independent of changes in miR-145 abundance. Our results show that miR-145 is selectively misregulated in HGPS and that the consequent up-regulation of LOX is causal for premature arterial stiffening and cardiac dysfunction.

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

2011 ◽  
Vol 39 (6) ◽  
pp. 1764-1769 ◽  
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.

The Transplantation of Ovaries between Genetically Sterile and Wild Type Drosophila melanogaste

1965 ◽  
Vol 20 (4) ◽  
pp. 292-297 ◽  
Author(s):  
Robert C. King ◽  
Dietrich Bodenstein
Keyword(s):  
Drosophila Melanogaster ◽  
Body Cavity ◽  
Ovarian Tumors ◽  
Wild Type ◽  
Adult Females ◽  
Recessive Genes ◽  
Initiating Factors ◽  
Adult Drosophila ◽  
Do So ◽  
Drosophila Melanogaste

Ovarian tumors are characteristically found in adult Drosophila melanogaster females homozygous for certain recessive genes (fes, nw and fu). Ovaries genetically destined to become tumorous do so even when they are transplanted to a normal abdomen. Normal ovaries transplanted to the abdomen of females homozygous for such tumor genes do not become tumorous. Therefore there is no evidence for diffusible tumorigenic agents as initiating factors in the development of the ovarian tumors characteristic of females homozygous for fes, nw or fu. Vitellogenesis is retarded in adult females homozygous for certain recessive genes (fs 2.1, ty and ap4). Transplantation of ovaries from homozygous females to the abdominal body cavity of females carrying the + alleles of the gene in question fails to cure the implant in the case of fs 2.1 and ty. Ovaries of ap4/ap4 genotype produce abundant yolk when implanted into wild type abdomens. Thus it is the abdominal environment of ap4 which is at fault, rather than a malfunctioning of the ovary.

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