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Biochemical Society Transactions Dec 2011A common feature of progeria syndromes is a premature aging phenotype and an enhanced accumulation of DNA damage arising from a compromised repair system. HGPS... (Review)
Review
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.
Topics: Aging; Animals; Cellular Senescence; DNA Damage; Humans; Lamins; Progeria; Signal Transduction
PubMed: 22103522
DOI: 10.1042/BST20110687 -
Journal of Cachexia, Sarcopenia and... Dec 2022Fibro-adipogenic progenitors (FAPs) in the muscles have been found to interact closely with muscle progenitor/stem cells (MPCs) and facilitate muscle regeneration at...
BACKGROUND
Fibro-adipogenic progenitors (FAPs) in the muscles have been found to interact closely with muscle progenitor/stem cells (MPCs) and facilitate muscle regeneration at normal conditions. However, it is not clear how FAPs may interact with MPCs in aged muscles. Senolytics have been demonstrated to selectively eliminate senescent cells and generate therapeutic benefits on ageing and multiple age-related disease models.
METHODS
By studying the muscles and primary cells of age matched WT mice and Zmpste24 (Z24 ) mice, an accelerated ageing model for Hutchinson-Gilford progeria syndrome (HGPS), we examined the interaction between FAPs and MPCs in progeria-aged muscle, and the potential effect of senolytic drug fisetin in removing senescent FAPs and improving the function of MPCs.
RESULTS
We observed that, compared with muscles of WT mice, muscles of Z24 mice contained a significantly increased number of FAPs (2.4-fold; n > =6, P < 0.05) and decreased number of MPCs (2.8-fold; n > =6, P < 0.05). FAPs isolated from Z24 muscle contained about 44% SA-β-gal+ senescent cells, in contrast to about 3.5% senescent cells in FAPs isolated from WT muscle (n > =6, P < 0.001). The co-culture of Z24 FAPs with WT MPCs resulted in impaired proliferation and myogenesis potential of WT MPCs, with the number of BrdU positive proliferative cells being reduced for 3.3 times (n > =6, P < 0.001) and the number of myosin heavy chain (MHC)-positive myotubes being reduced for 4.5 times (n > =6, P < 0.001). The treatment of the in vitro co-culture system of Z24 FAPs and WT MPCs with the senolytic drug fisetin led to increased apoptosis of Z24 FAPs (14.5-fold; n > =6, P < 0.001) and rescued the impaired function of MPCs by increasing the number of MHC-positive myotubes for 3.1 times (n > =6, P < 0.001). Treatment of Z24 mice with fisetin in vivo was effective in reducing the number of senescent FAPs (2.2-fold, n > =6, P < 0.05) and restoring the number of muscle stem cells (2.6-fold, n > =6, P < 0.05), leading to improved muscle pathology in Z24 mice.
CONCLUSIONS
These results indicate that the application of senolytics in the progeria-aged muscles can be an efficient strategy to remove senescent cells, including senescent FAPs, which results in improved function of muscle progenitor/stem cells. The senescent FAPs can be a potential novel target for therapeutic treatment of progeria ageing related muscle diseases.
Topics: Mice; Animals; Progeria; Senotherapeutics; Adipogenesis; Satellite Cells, Skeletal Muscle; Muscle Fibers, Skeletal
PubMed: 36218080
DOI: 10.1002/jcsm.13101 -
Cell Mar 2012Dysregulation of splicing and alternative splicing underlies many genetic and acquired diseases. We present an overview of recent strategies and successes in modulating... (Review)
Review
Dysregulation of splicing and alternative splicing underlies many genetic and acquired diseases. We present an overview of recent strategies and successes in modulating splicing therapeutically in clinical and preclinical contexts. Effective approaches include restoring open reading frames, influencing alternative splicing, and inducing exon inclusion to generate beneficial proteins and remove deleterious ones.
Topics: Alternative Splicing; Animals; Disease; Genetic Therapy; Humans; Muscular Dystrophies; Mutation; Neoplasms; Oligonucleotides, Antisense; Progeria; RNA Splicing
PubMed: 22424220
DOI: 10.1016/j.cell.2012.02.014 -
Nucleus (Austin, Tex.) Jan 2018Hutchinson-Gilford progeria syndrome (HGPS) is a sporadic, autosomal dominant disorder characterized by premature and accelerated aging symptoms leading to death at the... (Review)
Review
Hutchinson-Gilford progeria syndrome (HGPS) is a sporadic, autosomal dominant disorder characterized by premature and accelerated aging symptoms leading to death at the mean age of 14.6 years usually due to cardiovascular complications. HGPS is caused by a de novo point mutation in the LMNA gene encoding the intermediate filament proteins lamins A and C which are structural components of the nuclear lamina. This mutation leads to the production of a truncated toxic form of lamin A, issued from aberrant splicing and called progerin. Progerin accumulates in HGPS cells' nuclei and is a hallmark of the disease. Small amounts of progerin are also produced during normal aging. HGPS cells and animal preclinical models have provided insights into the molecular and cellular pathways that underlie the disease and have also highlighted possible mechanisms involved in normal aging. This review reports recent medical advances and treatment approaches for patients affected with HGPS.
Topics: Animals; Cell Nucleus; Humans; Mutation; Progeria
PubMed: 29619863
DOI: 10.1080/19491034.2018.1460045 -
Cell Jan 2021The ultra-rare, pediatric premature aging disorder Hutchinson-Gilford progeria syndrome (HGPS) is caused by mutation of LMNA, encoding the nuclear architectural protein...
The ultra-rare, pediatric premature aging disorder Hutchinson-Gilford progeria syndrome (HGPS) is caused by mutation of LMNA, encoding the nuclear architectural protein lamin A. Patients develop atherosclerosis and typically die of heart failure in their teens. FDA-approved Zokinvy prevents farnesylation of lamin A, reduces vascular stiffness, and extends survival in HGPS patients. To view this Bench to Bedside, open or download the PDF.
Topics: Enzyme Inhibitors; Farnesyltranstransferase; Humans; Molecular Targeted Therapy; Progeria
PubMed: 33482093
DOI: 10.1016/j.cell.2020.12.029 -
Nature Communications Nov 2022Defects in RNA splicing have been linked to human disorders, but remain poorly explored in inflammatory bowel disease (IBD). Here, we report that expression of the...
Defects in RNA splicing have been linked to human disorders, but remain poorly explored in inflammatory bowel disease (IBD). Here, we report that expression of the chromatin and alternative splicing regulator HP1γ is reduced in ulcerative colitis (UC). Accordingly, HP1γ gene inactivation in the mouse gut epithelium triggers IBD-like traits, including inflammation and dysbiosis. In parallel, we find that its loss of function broadly increases splicing noise, favoring the usage of cryptic splice sites at numerous genes with functions in gut biology. This results in the production of progerin, a toxic splice variant of prelamin A mRNA, responsible for the Hutchinson-Gilford Progeria Syndrome of premature aging. Splicing noise is also extensively detected in UC patients in association with inflammation, with progerin transcripts accumulating in the colon mucosa. We propose that monitoring HP1γ activity and RNA splicing precision can help in the management of IBD and, more generally, of accelerated aging.
Topics: Humans; Mice; Animals; Chromobox Protein Homolog 5; Colitis, Ulcerative; RNA Splicing; Progeria; Inflammation
PubMed: 36400769
DOI: 10.1038/s41467-022-34556-3 -
Aging Cell Feb 2019Hutchinson-Gilford Progeria Syndrome (HGPS) is a devastating premature aging disease. Mouse models have been instrumental for understanding HGPS mechanisms and for...
Hutchinson-Gilford Progeria Syndrome (HGPS) is a devastating premature aging disease. Mouse models have been instrumental for understanding HGPS mechanisms and for testing therapies, which to date have had only marginal benefits in mice and patients. Barriers to developing effective therapies include the unknown etiology of progeria mice early death, seemingly unrelated to the reported atherosclerosis contributing to HGPS patient mortality, and mice not recapitulating the severity of human disease. Here, we show that progeria mice die from starvation and cachexia. Switching progeria mice approaching death from regular diet to high-fat diet (HFD) rescues early lethality and ameliorates morbidity. Critically, feeding the mice only HFD delays aging and nearly doubles lifespan, which is the greatest lifespan extension recorded in progeria mice. The extended lifespan allows for progeria mice to develop degenerative aging pathologies of a severity that emulates the human disease. We propose that starvation and cachexia greatly influence progeria phenotypes and that nutritional/nutraceutical strategies might help modulate disease progression. Importantly, progeria mice on HFD provide a more clinically relevant animal model to study mechanisms of HGPS pathology and to test therapies.
Topics: Animals; Diet, High-Fat; Feeding Behavior; Humans; Lamin Type A; Longevity; Mice, Inbred C57BL; Mutation; Phenotype; Progeria
PubMed: 30548460
DOI: 10.1111/acel.12852 -
Genes Jan 2022Alternative splicing (AS) is a biological operation that enables a messenger RNA to encode protein variants (isoforms) that give one gene several functions or... (Review)
Review
Alternative splicing (AS) is a biological operation that enables a messenger RNA to encode protein variants (isoforms) that give one gene several functions or properties. This process provides one of the major sources of use for understanding the proteomic diversity of multicellular organisms. In combination with post-translational modifications, it contributes to generating a variety of protein-protein interactions (PPIs) that are essential to cellular homeostasis or proteostasis. However, cells exposed to many kinds of stresses (aging, genetic changes, carcinogens, etc.) sometimes derive cancer or disease onset from aberrant PPIs caused by DNA mutations. In this review, we summarize how splicing variants may form a neomorphic protein complex and cause diseases such as Hutchinson-Gilford progeria syndrome (HGPS) and small cell lung cancer (SCLC), and we discuss how protein-protein interfaces obtained from the variants may represent efficient therapeutic target sites to treat HGPS and SCLC.
Topics: Drug Delivery Systems; Humans; Lamin Type A; Lung Neoplasms; Progeria; Proteomics; Small Cell Lung Carcinoma
PubMed: 35205210
DOI: 10.3390/genes13020165 -
International Journal of Molecular... Jul 2021Hutchinson-Gilford progeria syndrome (HGPS), or progeria, is an extremely rare disorder that belongs to the class of laminopathies, diseases characterized by alterations... (Review)
Review
Hutchinson-Gilford progeria syndrome (HGPS), or progeria, is an extremely rare disorder that belongs to the class of laminopathies, diseases characterized by alterations in the genes that encode for the lamin proteins or for their associated interacting proteins. In particular, progeria is caused by a point mutation in the gene that codifies for the lamin A gene. This mutation ultimately leads to the biosynthesis of a mutated version of lamin A called progerin, which accumulates abnormally in the nuclear lamina. This accumulation elicits several alterations at the nuclear, cellular, and tissue levels that are phenotypically reflected in a systemic disorder with important alterations, mainly in the cardiovascular system, bones, skin, and overall growth, which results in premature death at an average age of 14.5 years. In 2020, lonafarnib became the first (and only) FDA approved drug for treating progeria. In this context, the present review focuses on the different therapeutic strategies currently under development, with special attention to the new small molecules described in recent years, which may represent the upcoming first-in-class drugs with new mechanisms of action endowed with effectiveness not only to treat but also to cure progeria.
Topics: Aging; Aging, Premature; Cell Nucleus; Cellular Senescence; Fibroblasts; Humans; Lamin Type A; Laminopathies; Mutation; Nuclear Lamina; Phenotype; Piperidines; Progeria; Pyridines; Skin; Small Molecule Libraries
PubMed: 34281245
DOI: 10.3390/ijms22137190 -
Current Biology : CB Mar 2007
Topics: Animals; Cell Nucleus; Chromatin; Gene Expression Regulation; Humans; Lamin Type A; Mutation; Neuromuscular Diseases; Nuclear Envelope; Nuclear Lamina; Nuclear Proteins; Progeria
PubMed: 17339009
DOI: 10.1016/j.cub.2006.12.035