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https://www.readbyqxmd.com/read/29051264/protein-sequestration-at-the-nuclear-periphery-as-a-potential-regulatory-mechanism-in-premature-aging
#1
REVIEW
Leonid Serebryannyy, Tom Misteli
Despite the extensive description of numerous molecular changes associated with aging, insights into the driver mechanisms of this fundamental biological process are limited. Based on observations in the premature aging syndrome Hutchinson-Gilford progeria, we explore the possibility that protein regulation at the inner nuclear membrane and the nuclear lamina contributes to the aging process. In support, sequestration of nucleoplasmic proteins to the periphery impacts cell stemness, the response to cytotoxicity, proliferation, changes in chromatin state, and telomere stability...
October 19, 2017: Journal of Cell Biology
https://www.readbyqxmd.com/read/29047356/non-syndromic-cardiac-progeria-in-a-patient-with-the-rare-pathogenic-p-asp300asn-variant-in-the-lmna-gene
#2
Ali J Marian
BACKGROUND: Mutations in LMNA gene, encoding Lamin A/C, cause a diverse array of phenotypes, collectively referred to as laminopathies. The most common manifestation is dilated cardiomyopathy (DCM), occurring in conjunction with variable skeletal muscle involvement but without involvement of the coronary arteries. Much less commonly, LMNA mutations cause progeroid syndromes, whereby an early-onset coronary artery disease (CAD) is the hallmark of the disease. We report a hitherto unreported compound cardiac phenotype, dubbed as "non-syndromic cardiac progeria", in a young patient who carried a rare pathogenic variant in the LMNA gene and developed progressive degeneration of various cardiac structures, as seen in the elderly...
October 18, 2017: BMC Medical Genetics
https://www.readbyqxmd.com/read/29029393/intermittent-treatment-with-farnesyltransferase-inhibitor-and-sulforaphane-improves-cellular-homeostasis-in-hutchinson-gilford-progeria-fibroblasts
#3
Diana Gabriel, Dinah Dorith Shafry, Leslie B Gordon, Karima Djabali
Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic condition associated with mutations in the LMNA gene. This disease recapitulates some aspects of normal aging, such as hair loss, thin skin, joint stiffness, and atherosclerosis. The latter leads to heart attack or stroke that causes death at an average age of 14.6 years in children with HGPS. The typical LMNA mutation results in the production of a truncated prelamin A protein, progerin, that remains permanently farnesylated and abnormally associated with the nuclear envelope...
September 12, 2017: Oncotarget
https://www.readbyqxmd.com/read/28990109/mir%C3%A2-342%C3%A2-5p-promotes-zmpste24%C3%A2-deficient-mouse-embryonic-fibroblasts-proliferation-by-suppressing-gas2
#4
Chun-Long Zhang, Xinguang Liu, Qiu-Jing He, Huiling Zheng, Shun Xu, Xing-Dong Xiong, Yuan Yuan, Jie Ruan, Jiang-Bin Li, Yu Xing, Zhongjun Zhou, Shixiong Deng
Cellular senescence is an irreversible growth arrest of cells that maintain their metabolic activities. Premature senescence can be induced by different stress factors and occurs in mouse embryonic fibroblasts (MEFs) derived from Zmpste24 metalloproteinase‑deficient mice, a progeria mouse model of Hutchinson‑Gilford Progeria Syndrome. Previous studies have shown that miR‑342‑5p, an intronic microRNA (miRNA/miR) reportedly involved in ageing associated diseases, is downregulated in Zmpste24‑/‑ MEFs...
October 5, 2017: Molecular Medicine Reports
https://www.readbyqxmd.com/read/28974341/bubr1-insufficiency-impairs-angiogenesis-in-aging-and-in-experimental-critical-limb-ischemic-mice
#5
Jun Okadome, Takuya Matsumoto, Keiji Yoshiya, Daisuke Matsuda, Kouji Tamada, Mitsuho Onimaru, Kaku Nakano, Kensuke Egashira, Yoshikazu Yonemitsu, Yoshihiko Maehara
OBJECTIVES: Budding uninhibited by benzimidazole-related 1 (BubR1), a cell cycle-related protein, is an essential component of the spindle checkpoint that regulates cell division. Mice in which BubR1 expression is reduced to 10% of the normal level display the phenotypic features of progeria. However, the role of BubR1 in vascular diseases and angiogenesis remains unknown. To investigate the influence of BubR1 on angiogenesis, we generated a low-null-BubR1-expressing (BubR1(L/-)) mouse strain with reduced BubR1 expression as low as 15% of the normal level without any abnormalities in appearance...
September 30, 2017: Journal of Vascular Surgery
https://www.readbyqxmd.com/read/28944914/gene-screening-facilitates-diagnosis-of-complicated-symptoms-a-case-report
#6
Hong Duan, Di Zhang, Jing Cheng, Yu Lu, Huijun Yuan
Gene mutation has an important role in disease pathogenesis; therefore, genetic screening is a useful tool for diagnosis. The present study screened pathogenic genes, ectodysplasin A (EDA) and lamin A/C (LMNA), in a patient with suspected syndromic hearing impairment and various other symptoms including tooth and skin abnormalities. Large‑scale sequencing of 438 deafness‑associated genes and whole‑genome sequencing was also performed. The present findings did not identify copy number variation and mutations in EDA; therefore, excluding the possibility of EDA‑initiated ectodermal dysplasia syndrome...
September 22, 2017: Molecular Medicine Reports
https://www.readbyqxmd.com/read/28934587/aging-in-the-cardiovascular-system-lessons-from-hutchinson-gilford-progeria-syndrome
#7
Magda R Hamczyk, Lara Del Campo, Vicente Andrés
Aging, the main risk factor for cardiovascular disease (CVD), is becoming progressively more prevalent in our societies. A better understanding of how aging promotes CVD is therefore urgently needed to develop new strategies to reduce disease burden. Atherosclerosis and heart failure contribute significantly to age-associated CVD-related morbimortality. CVD and aging are both accelerated in patients suffering from Hutchinson-Gilford progeria syndrome (HGPS), a rare genetic disorder caused by the prelamin A mutant progerin...
September 20, 2017: Annual Review of Physiology
https://www.readbyqxmd.com/read/28915791/segmentation-and-classification-of-two-channel-c-elegans-nucleus-labeled-fluorescence-images
#8
Mengdi Zhao, Jie An, Haiwen Li, Jiazhi Zhang, Shang-Tong Li, Xue-Mei Li, Meng-Qiu Dong, Heng Mao, Louis Tao
BACKGROUND: Aging is characterized by a gradual breakdown of cellular structures. Nuclear abnormality is a hallmark of progeria in human. Analysis of age-dependent nuclear morphological changes in Caenorhabditis elegans is of great value to aging research, and this calls for an automatic image processing method that is suitable for both normal and abnormal structures. RESULTS: Our image processing method consists of nuclear segmentation, feature extraction and classification...
September 15, 2017: BMC Bioinformatics
https://www.readbyqxmd.com/read/28905970/on-the-discovery-of-new-potent-human-farnesyltransferase-inhibitors-emerging-pyroglutamic-derivatives
#9
Germain Homerin, Emmanuelle Lipka, Benoît Rigo, Amaury Farce, Joëlle Dubois, Alina Ghinet
In the current context of lack of emergence of innovative human farnesyltransferase inhibitors families, and given all new therapeutic perspectives that open up for such molecules in rare diseases (e.g. Hutchinson-Gilford progeria syndrome), and in delta hepatitis, cardiovascular or neuroinflammatory diseases, we have just discovered a new series of powerful inhibitors. These molecules are pyroglutamic acid derivatives, and were evaluated on human farnesyltransferase in vitro then modeled in silico on the active site of the protein...
October 4, 2017: Organic & Biomolecular Chemistry
https://www.readbyqxmd.com/read/28878338/the-clinical-characteristics-of-asian-patients-with-classical-type-hutchinson-gilford-progeria-syndrome
#10
Nanae Sato-Kawano, Minoru Takemoto, Emiko Okabe, Koutaro Yokote, Muneaki Matsuo, Rika Kosaki, Kenji Ihara
Hutchinson-Gilford progeria syndrome (HGPS) is an extremely rare genetic disorder that shows a characteristic progeria phenotype. We conducted a questionnaire survey of 1173 tertiary hospitals in Japan and reviewed the academic reports, to identify the characteristics of Asian patients with classical HGPS. As a result, four Japanese patients were identified; this was estimated to account for approximately two-third of the prevalence in Japan. Three Asian patients who had definitively been diagnosed with classical HGPS were identified in the literature; in total, the clinical characteristics of seven patients were evaluated...
September 7, 2017: Journal of Human Genetics
https://www.readbyqxmd.com/read/28857661/identification-of-novel-rna-isoforms-of-lmna
#11
Emily DeBoy, Madaiah Puttaraju, Parthav Jailwala, Manjula Kasoji, Maggie Cam, Tom Misteli
The nuclear lamina is a proteinaceous meshwork situated underneath the inner nuclear membrane and is composed of nuclear lamin proteins, which are type-V intermediate filaments. The LMNA gene gives rise to lamin A and lamin C through alternative splicing. Mutations in LMNA cause multiple diseases known as laminopathies, including Hutchinson-Gilford Progeria Syndrome (HGPS), a premature aging disorder caused by a point mutation that activates a cryptic 5' splice site in exon 11, resulting in a 150 bp deletion in the LMNA mRNA and the production of the dominant lamin A isoform progerin...
August 31, 2017: Nucleus
https://www.readbyqxmd.com/read/28855503/nucleolar-expansion-and-elevated-protein-translation-in-premature-aging
#12
Abigail Buchwalter, Martin W Hetzer
Premature aging disorders provide an opportunity to study the mechanisms that drive aging. In Hutchinson-Gilford progeria syndrome (HGPS), a mutant form of the nuclear scaffold protein lamin A distorts nuclei and sequesters nuclear proteins. We sought to investigate protein homeostasis in this disease. Here, we report a widespread increase in protein turnover in HGPS-derived cells compared to normal cells. We determine that global protein synthesis is elevated as a consequence of activated nucleoli and enhanced ribosome biogenesis in HGPS-derived fibroblasts...
August 30, 2017: Nature Communications
https://www.readbyqxmd.com/read/28846075/dysfunction-of-the-mdm2-p53-axis-is-linked-to-premature-aging
#13
Davor Lessel, Danyi Wu, Carlos Trujillo, Thomas Ramezani, Ivana Lessel, Mohammad K Alwasiyah, Bidisha Saha, Fuki M Hisama, Katrin Rading, Ingrid Goebel, Petra Schütz, Günter Speit, Josef Högel, Holger Thiele, Gudrun Nürnberg, Peter Nürnberg, Matthias Hammerschmidt, Yan Zhu, David R Tong, Chen Katz, George M Martin, Junko Oshima, Carol Prives, Christian Kubisch
The tumor suppressor p53, a master regulator of the cellular response to stress, is tightly regulated by the E3 ubiquitin ligase MDM2 via an autoregulatory feedback loop. In addition to its well-established role in tumorigenesis, p53 has also been associated with aging in mice. Several mouse models with aberrantly increased p53 activity display signs of premature aging. However, the relationship between dysfunction of the MDM2/p53 axis and human aging remains elusive. Here, we have identified an antiterminating homozygous germline mutation in MDM2 in a patient affected by a segmental progeroid syndrome...
October 2, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28840549/approaches-for-identifying-novel-targets-in-precision-medicine-lessons-from-dna-repair
#14
Dean T Williams, Christopher J Staples
Genome stability is maintained by a number of elegant mechanisms, which sense and repair damaged DNA. Germline defects that compromise genomic integrity result in cancer predisposition, exemplified by rare syndromes caused by mutations in certain DNA repair genes. These individuals often exhibit other symptoms including progeria and neurodegeneration. Paradoxically, some of these deleterious genetic alterations provide novel therapeutic opportunities to target cancer cells; an excellent example of such an approach being the recent development of poly (ADP-ribose) polymerase inhibitors as the first 'synthetic lethal' medicine for patients with BRCA-mutant cancers...
2017: Advances in Experimental Medicine and Biology
https://www.readbyqxmd.com/read/28830687/senescent-intervertebral-disc-cells-exhibit-perturbed-matrix-homeostasis-phenotype
#15
Kevin Ngo, Prashanti Patil, Sara J McGowan, Laura J Niedernhofer, Paul D Robbins, James Kang, Gwendolyn Sowa, Nam Vo
Aging greatly increases the risk for intervertebral disc degeneration (IDD) as a result of proteoglycan loss due to reduced synthesis and enhanced degradation of the disc matrix proteoglycan (PG). How disc matrix PG homeostasis becomes perturbed with age is not known. The goal of this study is to determine whether cellular senescence is a source of this perturbation. We demonstrated that disc cellular senescence is dramatically increased in the DNA repair-deficient Ercc1(-/Δ) mouse model of human progeria...
September 2017: Mechanisms of Ageing and Development
https://www.readbyqxmd.com/read/28811655/a-tissue-engineered-blood-vessel-model-of-hutchinson-gilford-progeria-syndrome-using-human-ipsc-derived-smooth-muscle-cells
#16
Leigh Atchison, Haoyue Zhang, Kan Cao, George A Truskey
Hutchison-Gilford Progeria Syndrome (HGPS) is a rare, accelerated aging disorder caused by nuclear accumulation of progerin, an altered form of the Lamin A gene. The primary cause of death is cardiovascular disease at about 14 years. Loss and dysfunction of smooth muscle cells (SMCs) in the vasculature may cause defects associated with HGPS. Due to limitations of 2D cell culture and mouse models, there is a need to develop improved models to discover novel therapeutics. To address this need, we produced a functional three-dimensional model of HGPS that replicates an arteriole-scale tissue engineered blood vessel (TEBV) using induced pluripotent stem cell (iPSC)-derived SMCs from an HGPS patient...
August 15, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28801801/nuclear-envelope-a-new-frontier-in-plant-mechanosensing
#17
REVIEW
Kateryna Fal, Atef Asnacios, Marie-Edith Chabouté, Olivier Hamant
In animals, it is now well established that forces applied at the cell surface are propagated through the cytoskeleton to the nucleus, leading to deformations of the nuclear structure and, potentially, to modification of gene expression. Consistently, altered nuclear mechanics has been related to many genetic disorders, such as muscular dystrophy, cardiomyopathy and progeria. In plants, the integration of mechanical signals in cell and developmental biology has also made great progress. Yet, while the link between cell wall stresses and cytoskeleton is consolidated, such cortical mechanical cues have not been integrated with the nucleoskeleton...
August 12, 2017: Biophysical Reviews
https://www.readbyqxmd.com/read/28792007/shared-molecular-and-cellular-mechanisms-of-premature-ageing-and-ageing-associated-diseases
#18
REVIEW
Nard Kubben, Tom Misteli
Ageing is the predominant risk factor for many common diseases. Human premature ageing diseases are powerful model systems to identify and characterize cellular mechanisms that underpin physiological ageing. Their study also leads to a better understanding of the causes, drivers and potential therapeutic strategies of common diseases associated with ageing, including neurological disorders, diabetes, cardiovascular diseases and cancer. Using the rare premature ageing disorder Hutchinson-Gilford progeria syndrome as a paradigm, we discuss here the shared mechanisms between premature ageing and ageing-associated diseases, including defects in genetic, epigenetic and metabolic pathways; mitochondrial and protein homeostasis; cell cycle; and stem cell-regenerative capacity...
October 2017: Nature Reviews. Molecular Cell Biology
https://www.readbyqxmd.com/read/28768969/werner-syndrome-and-diabetes-mellitus-accompanied-by-adrenal-cortex-cancer
#19
Momoyo Nishioka, Shinji Kamei, Tomoe Kinoshita, Junpei Sanada, Yoshiro Fushimi, Shintaro Irie, Yurie Hirata, Akihito Tanabe, Hidenori Hirukawa, Tomohiko Kimura, Atsushi Obata, Fuminori Tatsumi, Kenji Kohara, Masashi Shimoda, Shuhei Nakanishi, Tomoatsu Mune, Kohei Kaku, Hideaki Kaneto
Werner syndrome is a rare genetic disease characterized by progeria, diabetes mellitus, cataracts and various types of malignancy. However, there are few reports showing adrenal cortex cancer in subjects with Werner syndrome. We herein report an extremely rare case of Werner syndrome accompanied by adrenal cortex cancer. Based on the data obtained from blood samples, computed tomography, magnetic resonance imaging and (131)I adosterol scintigraphy, we diagnosed this subject with adrenal cortex cancer and Cushing's syndrome...
2017: Internal Medicine
https://www.readbyqxmd.com/read/28756152/ophthalmologic-features-of-progeria
#20
Iason S Mantagos, Monica E Kleinman, Mark W Kieran, Leslie B Gordon
PURPOSE: To establish the natural history of ophthalmic characteristics in Progeria patients and to determine incidence of ocular manifestations. DESIGN: Retrospective case series of patients with Progeria who were seen between 2007 and 2016. METHODS: Setting: Tertiary-care academic center. PATIENT POPULATION: Fourteen patients (28 eyes) with Hutchinson-Gilford Progeria syndrome were included for statistical analysis from a total of 84 patients who have been enrolled in clinical trials for Progeria at Boston Children's Hospital...
October 2017: American Journal of Ophthalmology
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