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https://www.readbyqxmd.com/read/29907918/farnesyltransferase-inhibitor-and-rapamycin-correct-aberrant-genome-organisation-and-decrease-dna-damage-respectively-in-hutchinson-gilford-progeria-syndrome-fibroblasts
#1
Mehmet U Bikkul, Craig S Clements, Lauren S Godwin, Martin W Goldberg, Ian R Kill, Joanna M Bridger
Hutchinson-Gilford progeria syndrome (HGPS) is a rare and fatal premature ageing disease in children. HGPS is one of several progeroid syndromes caused by mutations in the LMNA gene encoding the nuclear structural proteins lamins A and C. In classic HGPS the mutation G608G leads to the formation of a toxic lamin A protein called progerin. During post-translational processing progerin remains farnesylated owing to the mutation interfering with a step whereby the farnesyl moiety is removed by the enzyme ZMPSTE24...
June 15, 2018: Biogerontology
https://www.readbyqxmd.com/read/29904107/pathological-modelling-of-pigmentation-disorders-associated-with-hutchinson-gilford-progeria-syndrome-hgps-revealed-an-impaired-melanogenesis-pathway-in-ips-derived-melanocytes
#2
Alessandra Lo Cicero, Manoubia Saidani, Jennifer Allouche, Anne Laure Egesipe, Lucile Hoch, Celine Bruge, Sabine Sigaudy, Annachiara De Sandre-Giovannoli, Nicolas Levy, Christine Baldeschi, Xavier Nissan
Hutchinson-Gilford Progeria Syndrome (HGPS) is a rare genetic disorder that leads to premature aging. In this study, we used induced pluripotent stem cells to investigate the hypopigmentation phenotypes observed in patients with progeria. Accordingly, two iPS cell lines were derived from cells from HGPS patients and differentiated into melanocytes. Measurements of melanin content revealed a lower synthesis of melanin in HGPS melanocytes as compared to non-pathologic cells. Analysis of the melanosome maturation process by electron microscopy revealed a lower percentage of mature, fully pigmented melanosomes...
June 14, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29884649/impaired-dna-demethylation-of-c-ebp-sites-causes-premature-aging
#3
Andrea Schäfer, Bernadette Mekker, Medhavi Mallick, Viviana Vastolo, Emil Karaulanov, Dominik Sebastian, Carina von der Lippen, Bernd Epe, Damien J Downes, Carola Scholz, Christof Niehrs
Changes in DNA methylation are among the best-documented epigenetic alterations accompanying organismal aging. However, whether and how altered DNA methylation is causally involved in aging have remained elusive. GADD45α (growth arrest and DNA damage protein 45A) and ING1 (inhibitor of growth family member 1) are adapter proteins for site-specific demethylation by TET (ten-eleven translocation) methylcytosine dioxygenases. Here we show that Gadd45a/Ing1 double-knockout mice display segmental progeria and phenocopy impaired energy homeostasis and lipodystrophy characteristic of Cebp ( CCAAT/enhancer-binding protein ) mutants...
June 8, 2018: Genes & Development
https://www.readbyqxmd.com/read/29847796/modeling-late-onset-sporadic-alzheimer-s-disease-through-bmi1-deficiency
#4
Anthony Flamier, Jida El Hajjar, James Adjaye, Karl J Fernandes, Mohamed Abdouh, Gilbert Bernier
Late-onset sporadic Alzheimer's disease (AD) is the most prevalent form of dementia, but its origin remains poorly understood. The Bmi1/Ring1 protein complex maintains transcriptional repression of developmental genes through histone H2A mono-ubiquitination, and Bmi1 deficiency in mice results in growth retardation, progeria, and neurodegeneration. Here, we demonstrate that BMI1 is silenced in AD brains, but not in those with early-onset familial AD, frontotemporal dementia, or Lewy body dementia. BMI1 expression was also reduced in cortical neurons from AD patient-derived induced pluripotent stem cells but not in neurons overexpressing mutant APP and PSEN1...
May 29, 2018: Cell Reports
https://www.readbyqxmd.com/read/29794150/-zmpste24-missense-mutations-that-cause-progeroid-diseases-decrease-prelamin-a-cleavage-activity-and-or-protein-stability
#5
Eric D Spear, Ehr-Ting Hsu, Laiyin Nie, Elisabeth P Carpenter, Christine A Hrycyna, Susan Michaelis
The human zinc metalloprotease ZMPSTE24 is an integral membrane protein critical for the final step in the biogenesis of the nuclear scaffold protein lamin A, encoded by LMNA After farnesylation and carboxyl methylation of its C-terminal CAAX motif, the lamin A precursor, prelamin A, undergoes proteolytic removal of its modified C-terminal 15 amino acids by ZMPSTE24. Mutations in LMNA or ZMPSTE24 that impede this prelamin A cleavage step cause the premature aging disease Hutchinson-Gilford Progeria Syndrome (HGPS) and the related progeroid disorders mandibuloacral dysplasia-type B (MAD-B) and restrictive dermopathy (RD)...
May 24, 2018: Disease Models & Mechanisms
https://www.readbyqxmd.com/read/29779866/nucleolar-function-in-lifespan-regulation
#6
REVIEW
Varnesh Tiku, Adam Antebi
The nucleolus is a prominent membraneless organelle residing within the nucleus. The nucleolus has been regarded as a housekeeping structure mainly known for its role in ribosomal RNA (rRNA) production and ribosome assembly. However, accumulating evidence has revealed its functions in numerous cellular processes that control organismal physiology, thereby taking the nucleolus much beyond its conventional role in ribosome biogenesis. Perturbations in nucleolar functions have been associated with severe diseases such as cancer and progeria...
April 27, 2018: Trends in Cell Biology
https://www.readbyqxmd.com/read/29772801/ogt-o-glcnac-transferase-selectively-modifies-multiple-residues-unique-to-lamin-a
#7
Dan N Simon, Amanda Wriston, Qiong Fan, Jeffrey Shabanowitz, Alyssa Florwick, Tejas Dharmaraj, Sherket B Peterson, Yosef Gruenbaum, Cathrine R Carlson, Line M Grønning-Wang, Donald F Hunt, Katherine L Wilson
The LMNA gene encodes lamins A and C with key roles in nuclear structure, signaling, gene regulation, and genome integrity. Mutations in LMNA cause over 12 diseases ('laminopathies'). Lamins A and C are identical for their first 566 residues. However, they form separate filaments in vivo, with apparently distinct roles. We report that lamin A is β- O -linked N -acetylglucosamine- (O -GlcNAc)-modified in human hepatoma (Huh7) cells and in mouse liver. In vitro assays with purified O -GlcNAc transferase (OGT) enzyme showed robust O -GlcNAcylation of recombinant mature lamin A tails (residues 385⁻646), with no detectable modification of lamin B1, lamin C, or 'progerin' (Δ50) tails...
May 17, 2018: Cells
https://www.readbyqxmd.com/read/29752965/recq-helicase-disease-and-related-progeroid-syndromes-recq2018-meeting
#8
REVIEW
Junko Oshima, Hisaya Kato, Yoshiro Maezawa, Koutaro Yokote
Progeroid syndrome is a group of disorders characterized by the early onset of diseases that are associated with aging. Best known examples are Werner syndrome, which is adult onset and results from disease-causing DNA sequence variants in the RecQ helicase gene WRN, and Hutchison-Gilford progeria syndrome, which is childhood-onset and results from unique, recurrent disease-causing DNA sequence variants of the gene LMNA that encodes nuclear intermediate filaments. Related single gene RecQ disorders are Bloom syndrome and Rothmund-Thomson syndrome...
July 2018: Mechanisms of Ageing and Development
https://www.readbyqxmd.com/read/29718780/isoprenoids-and-protein-prenylation-implications-in-the-pathogenesis-and-therapeutic-intervention-of-alzheimer-s-disease
#9
Angela Jeong, Kiall Francis Suazo, W Gibson Wood, Mark D Distefano, Ling Li
The mevalonate-isoprenoid-cholesterol biosynthesis pathway plays a key role in human health and disease. The importance of this pathway is underscored by the discovery that two major isoprenoids, farnesyl and geranylgeranyl pyrophosphate, are required to modify an array of proteins through a process known as protein prenylation, catalyzed by prenyltransferases. The lipophilic prenyl group facilitates the anchoring of proteins in cell membranes, mediating protein-protein interactions and signal transduction...
June 2018: Critical Reviews in Biochemistry and Molecular Biology
https://www.readbyqxmd.com/read/29717979/boosting-atm-activity-alleviates-ageing-and-extends-lifespan-in-a-mouse-model-of-progeria
#10
Minxian Qian, Zuojun Liu, Linyuan Peng, Xiaolong Tang, Fanbiao Meng, Ying Ao, Mingyan Zhou, Ming Wang, Xinyue Cao, Baoming Qin, Zimei Wang, Zhongjun Zhou, Guangming Wang, Zhengliang Gao, Xu Jun, Baohua Liu
DNA damage accumulates with age (Lombard et al., 2005). However, whether and how robust DNA repair machinery promotes longevity is elusive. Here, we demonstrate that ATM-centered DNA damage response (DDR) progressively declines with senescence and age, while low dose of chloroquine (CQ) activates ATM, promotes DNA damage clearance, rescues age-related metabolic shift, and prolongs replicative lifespan. Molecularly, ATM phosphorylates SIRT6 deacetylase and thus prevents MDM2-mediated ubiquitination and proteasomal degradation...
May 2, 2018: ELife
https://www.readbyqxmd.com/read/29710166/association-of-lonafarnib-treatment-vs-no-treatment-with-mortality-rate-in-patients-with-hutchinson-gilford-progeria-syndrome
#11
COMPARATIVE STUDY
Leslie B Gordon, Heather Shappell, Joe Massaro, Ralph B D'Agostino, Joan Brazier, Susan E Campbell, Monica E Kleinman, Mark W Kieran
Importance: Hutchinson-Gilford progeria syndrome (HGPS) is an extremely rare fatal premature aging disease. There is no approved treatment. Objective: To evaluate the association of monotherapy using the protein farnesyltransferase inhibitor lonafarnib with mortality rate in children with HGPS. Design, Setting, and Participants: Cohort study comparing contemporaneous (birth date ≥1991) untreated patients with HGPS matched with treated patients by age, sex, and continent of residency using conditional Cox proportional hazards regression...
April 24, 2018: JAMA: the Journal of the American Medical Association
https://www.readbyqxmd.com/read/29710145/precision-medicine-and-progress-in-the-treatment-of-hutchinson-gilford-progeria-syndrome
#12
Fuki Marie Hisama, Junko Oshima
No abstract text is available yet for this article.
April 24, 2018: JAMA: the Journal of the American Medical Association
https://www.readbyqxmd.com/read/29703891/targeting-of-nat10-enhances-healthspan-in-a-mouse-model-of-human-accelerated-aging-syndrome
#13
Gabriel Balmus, Delphine Larrieu, Ana C Barros, Casey Collins, Monica Abrudan, Mukerrem Demir, Nicola J Geisler, Christopher J Lelliott, Jacqueline K White, Natasha A Karp, James Atkinson, Andrea Kirton, Matt Jacobsen, Dean Clift, Raphael Rodriguez, David J Adams, Stephen P Jackson
Hutchinson-Gilford Progeria Syndrome (HGPS) is a rare, but devastating genetic disease characterized by segmental premature aging, with cardiovascular disease being the main cause of death. Cells from HGPS patients accumulate progerin, a permanently farnesylated, toxic form of Lamin A, disrupting the nuclear shape and chromatin organization, leading to DNA-damage accumulation and senescence. Therapeutic approaches targeting farnesylation or aiming to reduce progerin levels have provided only partial health improvements...
April 27, 2018: Nature Communications
https://www.readbyqxmd.com/read/29696758/micrornas-in-hereditary-and-sporadic-premature-aging-syndromes-and-other-laminopathies
#14
REVIEW
Diane Frankel, Valérie Delecourt, Karim Harhouri, Annachiara De Sandre-Giovannoli, Nicolas Lévy, Elise Kaspi, Patrice Roll
Hereditary and sporadic laminopathies are caused by mutations in genes encoding lamins, their partners, or the metalloprotease ZMPSTE24/FACE1. Depending on the clinical phenotype, they are classified as tissue-specific or systemic diseases. The latter mostly manifest with several accelerated aging features, as in Hutchinson-Gilford progeria syndrome (HGPS) and other progeroid syndromes. MicroRNAs are small noncoding RNAs described as powerful regulators of gene expression, mainly by degrading target mRNAs or by inhibiting their translation...
April 25, 2018: Aging Cell
https://www.readbyqxmd.com/read/29690642/autophagic-removal-of-farnesylated-carboxy-terminal-lamin-peptides
#15
Xiang Lu, Karima Djabali
The mammalian nuclear lamina proteins—prelamin A- and B-type lamins—are post-translationally modified by farnesylation, endoproteolysis, and carboxymethylation at a carboxy-terminal CAAX (C, cysteine; a, aliphatic amino acid; X, any amino acid) motif. However, prelamin A processing into mature lamin A is a unique process because it results in the production of farnesylated and carboxymethylated peptides. In cells from patients with Hutchinson⁻Gilford progeria syndrome, the mutant prelamin A protein, progerin, cannot release its prenylated carboxyl-terminal moiety and therefore remains permanently associated with the nuclear envelope (NE), causing severe nuclear alterations and a dysmorphic morphology...
April 23, 2018: Cells
https://www.readbyqxmd.com/read/29619863/an-overview-of-treatment-strategies-for-hutchinson-gilford-progeria-syndrome
#16
Karim Harhouri, Diane Frankel, Catherine Bartoli, Patrice Roll, Annachiara De Sandre-Giovannoli, Nicolas Lévy
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...
January 1, 2018: Nucleus
https://www.readbyqxmd.com/read/29619860/progerin-phosphorylation-in-interphase-is-lower-and-less-mechanosensitive-than-lamin-a-c-in-ips-derived-mesenchymal-stem-cells
#17
Sangkyun Cho, Amal Abbas, Jerome Irianto, Irena L Ivanovska, Yuntao Xia, Manu Tewari, Dennis E Discher
Interphase phosphorylation of lamin-A,C depends dynamically on a cell's microenvironment, including the stiffness of extracellular matrix. However, phosphorylation dynamics is poorly understood for diseased forms such as progerin, a permanently farnesylated mutant of LMNA that accelerates aging of stiff and mechanically stressed tissues. Here, fine-excision alignment mass spectrometry (FEA-MS) is developed to quantify progerin and its phosphorylation levels in patient iPS cells differentiated to mesenchymal stem cells (MSCs)...
January 1, 2018: Nucleus
https://www.readbyqxmd.com/read/29602596/mechanisms-of-vascular-aging-what-can-we-learn-from-hutchinson-gilford-progeria-syndrome
#18
Lara Del Campo, Magda R Hamczyk, Vicente Andrés, José Martínez-González, Cristina Rodríguez
Aging is the main risk factor for cardiovascular disease (CVD). The increased prevalence of CVD is partly due to the global increase in life expectancy. In this context, it is essential to identify the mechanisms by which aging induces CVD, with the ultimate aim of reducing its incidence. Both atherosclerosis and heart failure significantly contribute to age-associated CVD morbidity and mortality. Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disorder caused by the synthesis of progerin, which is noted for accelerated aging and CVD...
May 2018: Clínica e Investigación en Arteriosclerosis
https://www.readbyqxmd.com/read/29582385/-1-h-13-c-and-15-n-backbone-resonance-assignment-of-the-lamin-c-terminal-region-specific-to-prelamin-a
#19
Florian Celli, Ambre Petitalot, Camille Samson, François-Xavier Theillet, Sophie Zinn-Justin
Lamins are the main components of the nucleoskeleton. They form a protein meshwork that underlies the inner nuclear membrane. Mutations in the LMNA gene coding for A-type lamins (lamins A and C) cause a large panel of human diseases, referred to as laminopathies. These diseases include muscular dystrophies, lipodystrophies and premature aging diseases. Lamin A exhibits a C-terminal region that is different from lamin C and is post-translationally modified. It is produced as prelamin A and it is then farnesylated, cleaved, carboxymethylated and cleaved again in order to become mature lamin A...
March 26, 2018: Biomolecular NMR Assignments
https://www.readbyqxmd.com/read/29581305/everolimus-rescues-multiple-cellular-defects-in-laminopathy-patient-fibroblasts
#20
Amanda J DuBose, Stephen T Lichtenstein, Noreen M Petrash, Michael R Erdos, Leslie B Gordon, Francis S Collins
LMNA encodes the A-type lamins that are part of the nuclear scaffold. Mutations in LMNA can cause a variety of disorders called laminopathies, including Hutchinson-Gilford progeria syndrome (HGPS), atypical Werner syndrome, and Emery-Dreifuss muscular dystrophy. Previous work has shown that treatment of HGPS cells with the mTOR inhibitor rapamycin or with the rapamycin analog everolimus corrects several of the phenotypes seen at the cellular level-at least in part by increasing autophagy and reducing the amount of progerin, the toxic form of lamin A that is overproduced in HGPS patients...
April 17, 2018: Proceedings of the National Academy of Sciences of the United States of America
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