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Aging Oct 2022Almost since the discovery that mutations in the LMNA gene, encoding the nuclear structure components lamin A and C, lead to Hutchinson-Gilford progeria syndrome, people...
Almost since the discovery that mutations in the LMNA gene, encoding the nuclear structure components lamin A and C, lead to Hutchinson-Gilford progeria syndrome, people have speculated that lamins may have a role in normal aging. The most common HPGS mutation creates a splice variant of lamin A, progerin, which promotes accelerated aging pathology. While some evidence exists that progerin accumulates with normal aging, an increasing body of work indicates that prelamin A, a precursor of lamin A prior to C-terminal proteolytic processing, accumulates with age and may be a driver of normal aging. Prelamin A shares properties with progerin and is also linked to a rare progeroid disease, restrictive dermopathy. Here, we describe mechanisms underlying changes in prelamin A with aging and lay out the case that this unprocessed protein impacts normative aging. This is important since intervention strategies can be developed to modify this pathway as a means to extend healthspan and lifespan.
Topics: Humans; Aging; Lamin Type A; Mutation; Progeria; Proteolysis; Lamins
PubMed: 36260869
DOI: 10.18632/aging.204342 -
Cells Sep 2019Ribosome biogenesis is one of the most energy demanding processes in the cell. In eukaryotes, the main steps of this process occur in the nucleolus and include... (Review)
Review
Ribosome biogenesis is one of the most energy demanding processes in the cell. In eukaryotes, the main steps of this process occur in the nucleolus and include pre-ribosomal RNA (pre-rRNA) processing, post-transcriptional modifications, and assembly of many non-ribosomal factors and ribosomal proteins in order to form mature and functional ribosomes. In yeast and humans, the nucleolar RNA acetyltransferase Kre33/NAT10 participates in different maturation events, such as acetylation and processing of 18S rRNA, and assembly of the 40S ribosomal subunit. Here, we review the structural and functional features of Kre33/NAT10 RNA acetyltransferase, and we underscore the importance of this enzyme in ribosome biogenesis, as well as in acetylation of non-ribosomal targets. We also report on the role of human NAT10 in Hutchinson-Gilford progeria syndrome.
Topics: Acetyltransferases; Active Transport, Cell Nucleus; Animals; Cell Nucleolus; Humans; N-Terminal Acetyltransferases; Nuclear Localization Signals; Progeria; RNA Processing, Post-Transcriptional; Saccharomyces cerevisiae Proteins
PubMed: 31491951
DOI: 10.3390/cells8091035 -
International Journal of Molecular... Dec 2022Ectopic calcification (EC) is characterized by an abnormal deposition of calcium phosphate crystals in soft tissues such as blood vessels, skin, and brain parenchyma. EC... (Review)
Review
Ectopic calcification (EC) is characterized by an abnormal deposition of calcium phosphate crystals in soft tissues such as blood vessels, skin, and brain parenchyma. EC contributes to significant morbidity and mortality and is considered a major health problem for which no effective treatments currently exist. In recent years, growing emphasis has been placed on the role of mitochondrial dysfunction and oxidative stress in the pathogenesis of EC. Impaired mitochondrial respiration and increased levels of reactive oxygen species can be directly linked to key molecular pathways involved in EC such as adenosine triphosphate homeostasis, DNA damage signaling, and apoptosis. While EC is mainly encountered in common diseases such as diabetes mellitus and chronic kidney disease, studies in rare hereditary EC disorders such as pseudoxanthoma elasticum or Hutchinson-Gilford progeria syndrome have been instrumental in identifying the precise etiopathogenetic mechanisms leading to EC. In this narrative review, we describe the current state of the art regarding the role of mitochondrial dysfunction and oxidative stress in hereditary EC diseases. In-depth knowledge of aberrant mitochondrial metabolism and its local and systemic consequences will benefit the research into novel therapies for both rare and common EC disorders.
Topics: Humans; Pseudoxanthoma Elasticum; Progeria; Oxidative Stress; Mitochondria; Reactive Oxygen Species
PubMed: 36499615
DOI: 10.3390/ijms232315288 -
Frontiers in Molecular Biosciences 2022DNA-protein crosslinks (DPCs) are deleterious DNA lesions that occur when proteins are covalently crosslinked to the DNA by the action of variety of agents like reactive... (Review)
Review
DNA-protein crosslinks (DPCs) are deleterious DNA lesions that occur when proteins are covalently crosslinked to the DNA by the action of variety of agents like reactive oxygen species, aldehydes and metabolites, radiation, and chemotherapeutic drugs. Unrepaired DPCs are blockades to all DNA metabolic processes. Specifically, during DNA replication, replication forks stall at DPCs and are vulnerable to fork collapse, causing DNA breakage leading to genome instability and cancer. Replication-coupled DPC repair involves DPC degradation by proteases such as SPRTN or the proteasome and the subsequent removal of DNA-peptide adducts by nucleases and canonical DNA repair pathways. SPRTN is a DNA-dependent metalloprotease that cleaves DPC substrates in a sequence-independent manner and is also required for translesion DNA synthesis following DPC degradation. Biallelic mutations in SPRTN cause Ruijs-Aalfs (RJALS) syndrome, characterized by hepatocellular carcinoma and segmental progeria, indicating the critical role for SPRTN and DPC repair pathway in genome maintenance. In this review, we will discuss the mechanism of replication-coupled DPC repair, regulation of SPRTN function and its implications in human disease and cancer.
PubMed: 35782873
DOI: 10.3389/fmolb.2022.916697 -
Aerospace Medicine and Human Performance Feb 2020Spaceflight Associated Neuro-ocular Syndrome (SANS) results from long-duration spaceflight and presents with a constellation of signs (e.g., optic disc edema, choroidal... (Review)
Review
Spaceflight Associated Neuro-ocular Syndrome (SANS) results from long-duration spaceflight and presents with a constellation of signs (e.g., optic disc edema, choroidal folds, globe flattening, refractive error shifts, etc.). Optic nerve tortuosity (ONT) has been detected in approximately 47% of astronauts after long-duration spaceflight but has not yet been fully analyzed. This review examines terrestrial ONT in order to better understand how the condition is caused and measured. References were identified by PubMed and ScienceDirect searches covering 1955 to October 2018 using the terms "optic nerve tortuosity," "optic nerve kinking," "optic disc torsion," "optic kinking," and "ocular torsion." Additional references were identified by searching relevant articles. ONT measurements have evolved and become more objective. One measure consists of meeting two criteria: 1) lack of optic nerve congruity in >1 coronal section; and 2) subarachnoid space dilation. This "criteria measure" is objective, sensitive, and specific for determining the presence of tortuosity. Another measure is the tortuosity index, which offers additional benefits by measuring the degree of ONT, including the potential to track changes over time. There are numerous terrestrial ONT causes, including intracranial hypertension, hydrocephalus, Chiari malformation, neurofibromatosis, glaucoma, and progeria, among others. To accurately measure ONT, it is crucial to adhere to objective, standardized techniques. The tortuosity index offers the potential to measure intraindividual change in ONT. Among the varied conditions associated with ONT, one commonality is pressure change. The impact of intracranial pressure on the vascular system and vice versa may offer insight into what is occurring in space.
Topics: Aerospace Medicine; Astronauts; Humans; Optic Nerve; Papilledema; Space Flight; Vision Disorders
PubMed: 31980047
DOI: 10.3357/AMHP.5406.2020 -
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 -
Recent Patents on Biotechnology 2021Hutchinson-Gilford progeria syndrome (HGPS), also known as progeria of childhood or progeria is a rare, rapid, autosomal dominant genetic disorder characterized by... (Review)
Review
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 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.
METHODS
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.
Topics: CRISPR-Cas Systems; Genetic Therapy; Humans; Patents as Topic; Progeria; Technology
PubMed: 34602042
DOI: 10.2174/1872208315666210928114720 -
Scientific Reports Oct 2023Alzheimer's Disease (AD) is a leading cause of dementia characterized by amyloid plaques and neurofibrillary tangles, and its pathogenesis remains unclear. Current...
Alzheimer's Disease (AD) is a leading cause of dementia characterized by amyloid plaques and neurofibrillary tangles, and its pathogenesis remains unclear. Current cellular models for AD often require several months to exhibit phenotypic features due to the lack of an aging environment in vitro. Lamin A is a key component of the nuclear lamina. Progerin, a truncated protein resulting from specific lamin A mutations, causes Hutchinson-Gilford Progeria Syndrome (HGPS), a disease that prematurely ages individuals. Studies have reported that lamin A expression is induced in the brains of AD patients, and overlapping cellular phenotypes have been observed between HGPS and AD cells. In this study, we investigated the effects of exogenous progerin expression on neural progenitor cells carrying familial AD mutations (FAD). Within three to four weeks of differentiation, these cells exhibited robust AD phenotypes, including increased tau phosphorylation, amyloid plaque accumulation, and an elevated Aβ42 to Aβ40 ratio. Additionally, progerin expression significantly increased AD cellular phenotypes such as cell death and cell cycle re-entry. Our results suggest that progerin expression could be used to create an accelerated model for AD development and drug screening.
Topics: Humans; Lamin Type A; Alzheimer Disease; Progeria; Aging; Cell Nucleus
PubMed: 37884611
DOI: 10.1038/s41598-023-45826-5 -
Aging Cell Jun 2024Hutchinson-Gilford progeria syndrome (HGPS) is a rare and fatal disease manifested by premature aging and aging-related phenotypes, making it a disease model for aging....
Hutchinson-Gilford progeria syndrome (HGPS) is a rare and fatal disease manifested by premature aging and aging-related phenotypes, making it a disease model for aging. The cellular machinery mediating age-associated phenotypes in HGPS remains largely unknown, resulting in limited therapeutic targets for HGPS. In this study, we showed that mitophagy defects impaired mitochondrial function and contributed to cellular markers associated with aging in mesenchymal stem cells derived from HGPS patients (HGPS-MSCs). Mechanistically, we discovered that mitophagy affected the aging-associated phenotypes of HGPS-MSCs by inhibiting the STING-NF-ĸB pathway and the downstream transcription of senescence-associated secretory phenotypes (SASPs). Furthermore, by utilizing UMI-77, an effective mitophagy inducer, we showed that mitophagy induction alleviated aging-associated phenotypes in HGPS and naturally aged mice. Collectively, our results uncovered that mitophagy defects mediated the aging-associated markers in HGPS, highlighted the function of mitochondrial homeostasis in HGPS progression, and suggested mitophagy as an intervention target for HGPS and aging.
Topics: Progeria; Mitophagy; Humans; Mice; Animals; Aging; Cellular Senescence
PubMed: 38482753
DOI: 10.1111/acel.14143