scholarly journals Imbalanced nucleocytoskeletal connections create common polarity defects in progeria and physiological aging

2019 ◽  
Vol 116 (9) ◽  
pp. 3578-3583 ◽  
Author(s):  
Wakam Chang ◽  
Yuexia Wang ◽  
G. W. Gant Luxton ◽  
Cecilia Östlund ◽  
Howard J. Worman ◽  
...  
Keyword(s):  
Accelerated Aging ◽  
Nuclear Movement ◽  
Prelamin A ◽  
Physiological Aging ◽  
3T3 Fibroblasts ◽  
Normal Individuals ◽  
Actin Cables ◽  
Progeria Syndrome ◽  
Hutchinson Gilford Progeria Syndrome ◽  
Nih 3T3

Studies of the accelerated aging disorder Hutchinson–Gilford progeria syndrome (HGPS) can potentially reveal cellular defects associated with physiological aging. HGPS results from expression and abnormal nuclear envelope association of a farnesylated, truncated variant of prelamin A called “progerin.” We surveyed the diffusional mobilities of nuclear membrane proteins to identify proximal effects of progerin expression. The mobilities of three proteins—SUN2, nesprin-2G, and emerin—were reduced in fibroblasts from children with HGPS compared with those in normal fibroblasts. These proteins function together in nuclear movement and centrosome orientation in fibroblasts polarizing for migration. Both processes were impaired in fibroblasts from children with HGPS and in NIH 3T3 fibroblasts expressing progerin, but were restored by inhibiting protein farnesylation. Progerin affected both the coupling of the nucleus to actin cables and the oriented flow of the cables necessary for nuclear movement and centrosome orientation. Progerin overexpression increased levels of SUN1, which couples the nucleus to microtubules through nesprin-2G and dynein, and microtubule association with the nucleus. Reducing microtubule-nuclear connections through SUN1 depletion or dynein inhibition rescued the polarity defects. Nuclear movement and centrosome orientation were also defective in fibroblasts from normal individuals over 60 y, and both defects were rescued by reducing the increased level of SUN1 in these cells or inhibiting dynein. Our results identify imbalanced nuclear engagement of the cytoskeleton (microtubules: high; actin filaments: low) as the basis for intrinsic cell polarity defects in HGPS and physiological aging and suggest that rebalancing the connections can ameliorate the defects.

scholarly journals Imbalanced Nucleocytoskeletal Connections Create Common Polarity Defects in Progeria and Physiological Aging

2018 ◽  
Author(s):  
Wakam Chang ◽  
Yuexia Wang ◽  
G.W. Gant Luxton ◽  
Cecilia Östlund ◽  
Howard J. Worman ◽  
...  
Keyword(s):  
Membrane Proteins ◽  
Cell Polarity ◽  
Nuclear Membrane ◽  
Cell Polarization ◽  
Premature Aging ◽  
Molecular Characteristics ◽  
Nuclear Movement ◽  
Prelamin A ◽  
Physiological Aging ◽  
Actin Cables

AbstractStudies of the accelerated aging disorder Hutchinson-Gilford progeria syndrome (HGPS) can potentially reveal cellular defects associated with physiological aging. HGPS results from expression and abnormal nuclear envelope association of a farnesylated, truncated variant of prelamin A called progerin. We surveyed the diffusional mobilities of nuclear membrane proteins to identify proximal effects of progerin expression. The mobilities of three proteins were reduced in fibroblasts from children with HGPS compared to normal fibroblasts: SUN2, nesprin-2G, and emerin. These proteins function together in nuclear movement and centrosome orientation in fibroblasts polarizing for migration. Both processes were impaired in fibroblasts from children with HGPS and in NIH3T3 fibroblasts expressing progerin, but were restored by inhibiting protein farnesylation. Progerin affected both the coupling of the nucleus to actin cables and the oriented flow of the cables necessary for nuclear movement and centrosome orientation. Progerin overexpression increased levels of SUN1, which couples the nucleus to microtubules through nesprin-2G and dynein, and microtubule association with the nucleus. Reducing microtubule-nuclear connections through SUN1 depletion or dynein inhibition rescued the polarity defects. Nuclear movement and centrosome orientation were also defective in fibroblasts from normal individuals over 60 years old and both defects were rescued by reducing the increased level of SUN1 in these cells or inhibiting dynein. Our results identify imbalanced nuclear engagement of the cytoskeleton (microtubules, high; actin filaments, low) as the basis for intrinsic cell polarity defects in HGPS and physiological aging and suggest that rebalancing the connections can ameliorate the defects.SignificanceThe rare, premature aging syndrome HGPS arises from expression of a pathological prelamin A variant, termed progerin. Studies of progerin may identify treatments for HGPS and reveal novel cellular and molecular characteristics of normal aging. Here, we show that progerin selectively affects mobilities of three nuclear membrane proteins, SUN2, nesprin-2G and emerin that position the nucleus and establish cell polarity essential for migration. We find that both processes are defective in fibroblasts from children with HGPS and aged (> 60 years) individuals. The mechanism underlying these defects is excessive interaction of the nucleus with microtubules. Our work identifies nuclear-based defects in cell polarization as intrinsic factors in premature and physiological aging and suggests means for correcting them.

scholarly journals Abolishing the prelamin A ZMPSTE24 cleavage site leads to progeroid phenotypes with near-normal longevity in mice

2021 ◽  
Author(s):  
Yuexia Wang ◽  
Khurts Shiladardi ◽  
Trunee Hsu ◽  
Kamsi O. Odinammadu ◽  
Takamitsu Maruyama ◽  
...  
Keyword(s):  
Nuclear Lamina ◽  
Lamin A ◽  
Protein Accumulation ◽  
Loss Of Function ◽  
Prelamin A ◽  
Protein Farnesyltransferase ◽  
Physiological Aging ◽  
Robust Model ◽  
Progeria Syndrome ◽  
Hutchinson Gilford Progeria Syndrome

Prelamin A is a farnesylated precursor of lamin A, a nuclear lamina protein. Accumulation of the farnesylated prelamin A variant progerin, with an internal deletion including its processing site, causes Hutchinson-Gilford progeria syndrome. Loss of function mutations in ZMPSTE24, which encodes the prelamin A processing enzyme, lead to accumulation of full-length farnesylated prelamin A and cause related progeroid disorders. Some data suggest that prelamin A also accumulates with physiological aging. Zmpste24-/- mice die young, at ~20 weeks. Because ZMPSTE24 has functions in addition to prelamin A processing, we generated a mouse model to examine effects solely due to the presence of permanently farnesylated prelamin A. These mice have an L648R amino acid substitution in prelamin A that blocks ZMPSTE24-catalyzed processing to lamin A. The LmnaL648R/L648R mice express only prelamin and no mature protein. Notably, nearly all survive to 65-70 weeks, with approximately 40% of male and 75% of female LmnaL648R/L648R having near-normal lifespans of almost 2 years. Starting at ~10 weeks of age, LmnaL648R/L648R mice of both sexes have lower body masses and body fat than controls. By ~20-30 weeks of age, they exhibit detectable cranial, mandibular and dental defects similar to those observed in Zmpste24-/- mice, and have decreased vertebral bone density compared to age- and sex-matched controls. Cultured embryonic fibroblasts from LmnaL648R/L648R mice have aberrant nuclear morphology that is reversible by treatment with a protein farnesyltransferase inhibitor. These novel mice provide a robust model to study the effects of farnesylated prelamin A during physiological aging.

scholarly journals High-Throughput Screen Detects Calcium Signaling Dysfunction in Hutchinson-Gilford Progeria Syndrome

2021 ◽  
Vol 22 (14) ◽  
pp. 7327
Author(s):  
Juan A. Fafián-Labora ◽  
Miriam Morente-López ◽  
Fco. Javier de Toro ◽  
María C. Arufe
Keyword(s):  
Calcium Signaling ◽  
Rare Disease ◽  
Cell Lines ◽  
Healthy Aging ◽  
Accelerated Aging ◽  
Cytosolic Calcium ◽  
Calcium Handling ◽  
Therapeutic Window ◽  
Progeria Syndrome ◽  
Hutchinson Gilford Progeria Syndrome

Hutchinson–Gilford progeria syndrome (HGPS) is a deadly childhood disorder, which is considered a very rare disease. It is caused by an autosomal dominant mutation on the LMNA gene, and it is characterized by accelerated aging. Human cell lines from HGPS patients and healthy parental controls were studied in parallel using next-generation sequencing (NGS) to unravel new non-previously altered molecular pathways. Nine hundred and eleven transcripts were differentially expressed when comparing healthy versus HGPS cell lines from a total of 21,872 transcripts; ITPR1, ITPR3, CACNA2D1, and CAMK2N1 stood out among them due to their links with calcium signaling, and these were validated by Western blot analysis. It was observed that the basal concentration of intracellular Ca2+ was statistically higher in HGPS cell lines compared to healthy ones. The relationship between genes involved in Ca2+ signaling and mitochondria-associated membranes (MAM) was demonstrated through cytosolic calcium handling by means of an automated fluorescent plate reading system (FlexStation 3, Molecular Devices), and apoptosis and mitochondrial ROS production were examined by means of flow cytometry analysis. Altogether, our data suggest that the Ca2+ signaling pathway is altered in HGPS at least in part due to the overproduction of reactive oxygen species (ROS). Our results unravel a new therapeutic window for the treatment of this rare disease and open new strategies to study pathologies involving both accelerated and healthy aging.

scholarly journals Activating the synthesis of progerin, the mutant prelamin A in Hutchinson–Gilford progeria syndrome, with antisense oligonucleotides

2009 ◽  
Vol 18 (13) ◽  
pp. 2462-2471 ◽  
Author(s):  
Loren G. Fong ◽  
Timothy A. Vickers ◽  
Emily A. Farber ◽  
Christine Choi ◽  
Ui Jeong Yun ◽  
...  
Keyword(s):  
Antisense Oligonucleotides ◽  
Prelamin A ◽  
Progeria Syndrome ◽  
Hutchinson Gilford Progeria Syndrome

scholarly journals Altered Nuclear Functions in Progeroid Syndromes: a Paradigm for Aging Research

2009 ◽  
Vol 9 ◽  
pp. 1449-1462 ◽  
Author(s):  
Baomin Li ◽  
Sonali Jog ◽  
Jose Candelario ◽  
Sita Reddy ◽  
Lucio Comai
Keyword(s):  
Werner Syndrome ◽  
Accelerated Aging ◽  
Natural Aging ◽  
Aging Research ◽  
Cellular Processes ◽  
Functional Connections ◽  
Age Related ◽  
Progeroid Syndromes ◽  
Progeria Syndrome ◽  
Hutchinson Gilford Progeria Syndrome

Syndromes of accelerated aging could provide an entry point for identifying and dissecting the cellular pathways that are involved in the development of age-related pathologies in the general population. However, their usefulness for aging research has been controversial, as it has been argued that these diseases do not faithfully reflect the process of natural aging. Here we review recent findings on the molecular basis of two progeroid diseases, Werner syndrome (WS) and Hutchinson-Gilford progeria syndrome (HGPS), and highlight functional connections to cellular processes that may contribute to normal aging.

A genome-wide CRISPR-based screen identifies KAT7 as a driver of cellular senescence

2021 ◽  
Vol 13 (575) ◽  
pp. eabd2655
Author(s):  
Wei Wang ◽  
Yuxuan Zheng ◽  
Shuhui Sun ◽  
Wei Li ◽  
Moshi Song ◽  
...  
Keyword(s):  
Cellular Senescence ◽  
Werner Syndrome ◽  
Embryonic Stem ◽  
Accelerated Aging ◽  
Premature Aging ◽  
Mesenchymal Precursor Cells ◽  
Genome Wide ◽  
A Genome ◽  
Progeria Syndrome ◽  
Hutchinson Gilford Progeria Syndrome

Understanding the genetic and epigenetic bases of cellular senescence is instrumental in developing interventions to slow aging. We performed genome-wide CRISPR-Cas9–based screens using two types of human mesenchymal precursor cells (hMPCs) exhibiting accelerated senescence. The hMPCs were derived from human embryonic stem cells carrying the pathogenic mutations that cause the accelerated aging diseases Werner syndrome and Hutchinson-Gilford progeria syndrome. Genes whose deficiency alleviated cellular senescence were identified, including KAT7, a histone acetyltransferase, which ranked as a top hit in both progeroid hMPC models. Inactivation of KAT7 decreased histone H3 lysine 14 acetylation, repressed p15INK4b transcription, and alleviated hMPC senescence. Moreover, lentiviral vectors encoding Cas9/sg-Kat7, given intravenously, alleviated hepatocyte senescence and liver aging and extended life span in physiologically aged mice as well as progeroid Zmpste24−/− mice that exhibit a premature aging phenotype. CRISPR-Cas9–based genetic screening is a robust method for systematically uncovering senescence genes such as KAT7, which may represent a therapeutic target for developing aging interventions.

scholarly journals Neurogenesis and brain aging

2019 ◽  
Vol 30 (6) ◽  
pp. 573-580 ◽  
Author(s):  
Nickolay K. Isaev ◽  
Elena V. Stelmashook ◽  
Elisaveta E. Genrikhs
Keyword(s):  
Brain Aging ◽  
Werner Syndrome ◽  
Accelerated Aging ◽  
Normal Aging ◽  
Postnatal Period ◽  
Human Aging ◽  
Distinctive Features ◽  
Progeria Syndrome ◽  
Hutchinson Gilford Progeria Syndrome ◽  
The Brain

AbstractHuman aging affects the entire organism, but aging of the brain must undoubtedly be different from that of all other organs, as neurons are highly differentiated postmitotic cells, for the majority of which the lifespan in the postnatal period is equal to the lifespan of the entire organism. In this work, we examine the distinctive features of brain aging and neurogenesis during normal aging, pathological aging (Alzheimer’s disease), and accelerated aging (Hutchinson-Gilford progeria syndrome and Werner syndrome).

Lamin A-linked progerias: is farnesylation the be all and end all?

2010 ◽  
Vol 38 (1) ◽  
pp. 281-286 ◽  
Author(s):  
Dawn T. Smallwood ◽  
Sue Shackleton
Keyword(s):  
Clinical Trials ◽  
Aging Process ◽  
Gene Mutations ◽  
Accelerated Aging ◽  
Membrane Dynamics ◽  
Lamin A ◽  
Farnesyltransferase Inhibitors ◽  
C Terminus ◽  
Progeria Syndrome ◽  
Hutchinson Gilford Progeria Syndrome

HGPS (Hutchinson–Gilford progeria syndrome) is a severe childhood disorder that appears to mimic an accelerated aging process. The disease is most commonly caused by gene mutations that disrupt the normal post-translational processing of lamin A, a structural component of the nuclear envelope. Impaired processing results in aberrant retention of a farnesyl group at the C-terminus of lamin A, leading to altered membrane dynamics. It has been widely proposed that persistence of the farnesyl moiety is the major factor responsible for the disease, prompting clinical trials of farnesyltransferase inhibitors to prevent lamin A farnesylation in children afflicted with HGPS. Although there is evidence implicating farnesylation in causing some of the cellular defects of HGPS, results of several recent studies suggest that aberrant lamin A farnesylation is not the only determinant of the disease. These findings have important implications for the design of treatments for this devastating disease.

scholarly journals MG132 induces progerin clearance and improves disease phenotypes in fibroblasts of patients affected with Hutchinson-Gilford Progeria-like syndromes

2021 ◽  
Author(s):  
Karim HARHOURI ◽  
Pierre CAU ◽  
Franck CASEY ◽  
Koffi Mawuse GUEDENON ◽  
Yassamine DOUBAJ ◽  
...  
Keyword(s):  
De Novo ◽  
Accelerated Aging ◽  
Therapeutic Trial ◽  
Cell Nuclei ◽  
Gene Encoding ◽  
Prelamin A ◽  
Exon 11 ◽  
Cellular Phenotypes ◽  
Carboxy Terminal ◽  
Hutchinson Gilford Progeria Syndrome

Progeroid Syndromes (PS), including Hutchinson-Gilford Progeria Syndrome (HGPS, OMIM #176670), are premature and accelerated aging that clinically resemble some aspects of advancing physiological aging. Most classical HGPS patients carry a de novo point mutation within exon 11 of the LMNA gene encoding A-type Lamins. This mutation activates a cryptic splice site leading to the deletion of 50 amino acids at its carboxy-terminal domain, resulting in a truncated and permanently farnesylated Prelamin A called Prelamin A Δ50 or Progerin that accumulates in HGPS cell nuclei and is a hallmark of the disease. Some patients with PS carry other LMNA mutations affecting exon 11 splicing, leading to defects in nuclear A-type Lamins and are named “HGPS-like” patients. They also produce Progerin and/or other truncated Prelamin A isoforms (Δ35 and & Δ90). We recently found that MG132, a proteasome inhibitor, induced progerin clearance in classical HGPS through autophagy activation and splicing regulation. Here, we show that MG132 induces aberrant prelamin A clearance and improves cellular phenotypes in HGPS-like patient cells. These results provide preclinical proof of principle for the use of a promising class of molecules toward a potential therapy for children with HGPS-like, who may therefore be eligible for inclusion in a therapeutic trial based on this approach, together with classical HGPS patients.

scholarly journals Epidermal expression of the truncated prelamin A causing Hutchinson-Gilford progeria syndrome: effects on keratinocytes, hair and skin

2008 ◽  
Vol 17 (15) ◽  
pp. 2357-2369 ◽  
Author(s):  
Y. Wang ◽  
A. A. Panteleyev ◽  
D. M. Owens ◽  
K. Djabali ◽  
C. L. Stewart ◽  
...  
Keyword(s):  
Prelamin A ◽  
Progeria Syndrome ◽  
Hutchinson Gilford Progeria Syndrome ◽  
Epidermal Expression
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