The Experts below are selected from a list of 5451 Experts worldwide ranked by ideXlab platform
Susan Michaelis - One of the best experts on this subject based on the ideXlab platform.
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lmna associated cardiocutaneous Progeria an inherited autosomal dominant premature aging syndrome with late onset
American Journal of Medical Genetics Part A, 2013Co-Authors: Megan S Kane, Mark E Lindsay, Daniel P Judge, Jemima Barrowman, Colette Ap M Rhys, Lisa Simonson, Harry C Dietz, Susan MichaelisAbstract:Hutchinson–Gilford Progeria Syndrome (HGPS) is a premature aging disorder caused by mutations in LMNA, which encodes the nuclear scaffold proteins lamin A and C. In HGPS and related Progerias, processing of prelamin A is blocked at a critical step mediated by the zinc metalloprotease ZMPSTE24. LMNA-linked Progerias can be grouped into two classes: (1) the processing-deficient, early onset “typical” Progerias (e.g., HGPS), and (2) the processing-proficient “atypical” Progeria syndromes (APS) that are later in onset. Here we describe a previously unrecognized Progeria syndrome with prominent cutaneous and cardiovascular manifestations belonging to the second class. We suggest the name LMNA-associated cardiocutaneous Progeria syndrome (LCPS) for this disorder. Affected patients are normal at birth but undergo progressive cutaneous changes in childhood and die in middle age of cardiovascular complications, including accelerated atherosclerosis, calcific valve disease, and cardiomyopathy. In addition, the proband demonstrated cancer susceptibility, a phenotype rarely described for LMNA-based Progeria disorders. The LMNA mutation that caused LCPS in this family is a heterozygous c.899A>G (p.D300G) mutation predicted to alter the coiled–coil domain of lamin A/C. In skin fibroblasts isolated from the proband, the processing and levels of lamin A and C are normal. However, nuclear morphology is aberrant and rescued by treatment with farnesyltransferase inhibitors, as is also the case for HGPS and other laminopathies. Our findings advance knowledge of human LMNA Progeria syndromes, and raise the possibility that typical and atypical Progerias may converge upon a common mechanism to cause premature aging disease. © 2013 Wiley Periodicals, Inc.
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LMNA‐associated cardiocutaneous Progeria: An inherited autosomal dominant premature aging syndrome with late onset
American Journal of Medical Genetics Part A, 2013Co-Authors: Megan S Kane, Mark E Lindsay, Daniel P Judge, Jemima Barrowman, Colette Ap M Rhys, Lisa Simonson, Harry C Dietz, Susan MichaelisAbstract:Hutchinson–Gilford Progeria Syndrome (HGPS) is a premature aging disorder caused by mutations in LMNA, which encodes the nuclear scaffold proteins lamin A and C. In HGPS and related Progerias, processing of prelamin A is blocked at a critical step mediated by the zinc metalloprotease ZMPSTE24. LMNA-linked Progerias can be grouped into two classes: (1) the processing-deficient, early onset “typical” Progerias (e.g., HGPS), and (2) the processing-proficient “atypical” Progeria syndromes (APS) that are later in onset. Here we describe a previously unrecognized Progeria syndrome with prominent cutaneous and cardiovascular manifestations belonging to the second class. We suggest the name LMNA-associated cardiocutaneous Progeria syndrome (LCPS) for this disorder. Affected patients are normal at birth but undergo progressive cutaneous changes in childhood and die in middle age of cardiovascular complications, including accelerated atherosclerosis, calcific valve disease, and cardiomyopathy. In addition, the proband demonstrated cancer susceptibility, a phenotype rarely described for LMNA-based Progeria disorders. The LMNA mutation that caused LCPS in this family is a heterozygous c.899A>G (p.D300G) mutation predicted to alter the coiled–coil domain of lamin A/C. In skin fibroblasts isolated from the proband, the processing and levels of lamin A and C are normal. However, nuclear morphology is aberrant and rescued by treatment with farnesyltransferase inhibitors, as is also the case for HGPS and other laminopathies. Our findings advance knowledge of human LMNA Progeria syndromes, and raise the possibility that typical and atypical Progerias may converge upon a common mechanism to cause premature aging disease. © 2013 Wiley Periodicals, Inc.
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LMNA-associated cardiocutaneous Progeria: an inherited autosomal dominant premature aging syndrome with late onset.
American journal of medical genetics. Part A, 2013Co-Authors: Megan S Kane, Mark E Lindsay, Daniel P Judge, Jemima Barrowman, Colette Ap M Rhys, Lisa Simonson, Harry C Dietz, Susan MichaelisAbstract:Hutchinson-Gilford Progeria Syndrome (HGPS) is a premature aging disorder caused by mutations in LMNA, which encodes the nuclear scaffold proteins lamin A and C. In HGPS and related Progerias, processing of prelamin A is blocked at a critical step mediated by the zinc metalloprotease ZMPSTE24. LMNA-linked Progerias can be grouped into two classes: (1) the processing-deficient, early onset "typical" Progerias (e.g., HGPS), and (2) the processing-proficient "atypical" Progeria syndromes (APS) that are later in onset. Here we describe a previously unrecognized Progeria syndrome with prominent cutaneous and cardiovascular manifestations belonging to the second class. We suggest the name LMNA-associated cardiocutaneous Progeria syndrome (LCPS) for this disorder. Affected patients are normal at birth but undergo progressive cutaneous changes in childhood and die in middle age of cardiovascular complications, including accelerated atherosclerosis, calcific valve disease, and cardiomyopathy. In addition, the proband demonstrated cancer susceptibility, a phenotype rarely described for LMNA-based Progeria disorders. The LMNA mutation that caused LCPS in this family is a heterozygous c.899A>G (p.D300G) mutation predicted to alter the coiled-coil domain of lamin A/C. In skin fibroblasts isolated from the proband, the processing and levels of lamin A and C are normal. However, nuclear morphology is aberrant and rescued by treatment with farnesyltransferase inhibitors, as is also the case for HGPS and other laminopathies. Our findings advance knowledge of human LMNA Progeria syndromes, and raise the possibility that typical and atypical Progerias may converge upon a common mechanism to cause premature aging disease.
Megan S Kane - One of the best experts on this subject based on the ideXlab platform.
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lmna associated cardiocutaneous Progeria an inherited autosomal dominant premature aging syndrome with late onset
American Journal of Medical Genetics Part A, 2013Co-Authors: Megan S Kane, Mark E Lindsay, Daniel P Judge, Jemima Barrowman, Colette Ap M Rhys, Lisa Simonson, Harry C Dietz, Susan MichaelisAbstract:Hutchinson–Gilford Progeria Syndrome (HGPS) is a premature aging disorder caused by mutations in LMNA, which encodes the nuclear scaffold proteins lamin A and C. In HGPS and related Progerias, processing of prelamin A is blocked at a critical step mediated by the zinc metalloprotease ZMPSTE24. LMNA-linked Progerias can be grouped into two classes: (1) the processing-deficient, early onset “typical” Progerias (e.g., HGPS), and (2) the processing-proficient “atypical” Progeria syndromes (APS) that are later in onset. Here we describe a previously unrecognized Progeria syndrome with prominent cutaneous and cardiovascular manifestations belonging to the second class. We suggest the name LMNA-associated cardiocutaneous Progeria syndrome (LCPS) for this disorder. Affected patients are normal at birth but undergo progressive cutaneous changes in childhood and die in middle age of cardiovascular complications, including accelerated atherosclerosis, calcific valve disease, and cardiomyopathy. In addition, the proband demonstrated cancer susceptibility, a phenotype rarely described for LMNA-based Progeria disorders. The LMNA mutation that caused LCPS in this family is a heterozygous c.899A>G (p.D300G) mutation predicted to alter the coiled–coil domain of lamin A/C. In skin fibroblasts isolated from the proband, the processing and levels of lamin A and C are normal. However, nuclear morphology is aberrant and rescued by treatment with farnesyltransferase inhibitors, as is also the case for HGPS and other laminopathies. Our findings advance knowledge of human LMNA Progeria syndromes, and raise the possibility that typical and atypical Progerias may converge upon a common mechanism to cause premature aging disease. © 2013 Wiley Periodicals, Inc.
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LMNA‐associated cardiocutaneous Progeria: An inherited autosomal dominant premature aging syndrome with late onset
American Journal of Medical Genetics Part A, 2013Co-Authors: Megan S Kane, Mark E Lindsay, Daniel P Judge, Jemima Barrowman, Colette Ap M Rhys, Lisa Simonson, Harry C Dietz, Susan MichaelisAbstract:Hutchinson–Gilford Progeria Syndrome (HGPS) is a premature aging disorder caused by mutations in LMNA, which encodes the nuclear scaffold proteins lamin A and C. In HGPS and related Progerias, processing of prelamin A is blocked at a critical step mediated by the zinc metalloprotease ZMPSTE24. LMNA-linked Progerias can be grouped into two classes: (1) the processing-deficient, early onset “typical” Progerias (e.g., HGPS), and (2) the processing-proficient “atypical” Progeria syndromes (APS) that are later in onset. Here we describe a previously unrecognized Progeria syndrome with prominent cutaneous and cardiovascular manifestations belonging to the second class. We suggest the name LMNA-associated cardiocutaneous Progeria syndrome (LCPS) for this disorder. Affected patients are normal at birth but undergo progressive cutaneous changes in childhood and die in middle age of cardiovascular complications, including accelerated atherosclerosis, calcific valve disease, and cardiomyopathy. In addition, the proband demonstrated cancer susceptibility, a phenotype rarely described for LMNA-based Progeria disorders. The LMNA mutation that caused LCPS in this family is a heterozygous c.899A>G (p.D300G) mutation predicted to alter the coiled–coil domain of lamin A/C. In skin fibroblasts isolated from the proband, the processing and levels of lamin A and C are normal. However, nuclear morphology is aberrant and rescued by treatment with farnesyltransferase inhibitors, as is also the case for HGPS and other laminopathies. Our findings advance knowledge of human LMNA Progeria syndromes, and raise the possibility that typical and atypical Progerias may converge upon a common mechanism to cause premature aging disease. © 2013 Wiley Periodicals, Inc.
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LMNA-associated cardiocutaneous Progeria: an inherited autosomal dominant premature aging syndrome with late onset.
American journal of medical genetics. Part A, 2013Co-Authors: Megan S Kane, Mark E Lindsay, Daniel P Judge, Jemima Barrowman, Colette Ap M Rhys, Lisa Simonson, Harry C Dietz, Susan MichaelisAbstract:Hutchinson-Gilford Progeria Syndrome (HGPS) is a premature aging disorder caused by mutations in LMNA, which encodes the nuclear scaffold proteins lamin A and C. In HGPS and related Progerias, processing of prelamin A is blocked at a critical step mediated by the zinc metalloprotease ZMPSTE24. LMNA-linked Progerias can be grouped into two classes: (1) the processing-deficient, early onset "typical" Progerias (e.g., HGPS), and (2) the processing-proficient "atypical" Progeria syndromes (APS) that are later in onset. Here we describe a previously unrecognized Progeria syndrome with prominent cutaneous and cardiovascular manifestations belonging to the second class. We suggest the name LMNA-associated cardiocutaneous Progeria syndrome (LCPS) for this disorder. Affected patients are normal at birth but undergo progressive cutaneous changes in childhood and die in middle age of cardiovascular complications, including accelerated atherosclerosis, calcific valve disease, and cardiomyopathy. In addition, the proband demonstrated cancer susceptibility, a phenotype rarely described for LMNA-based Progeria disorders. The LMNA mutation that caused LCPS in this family is a heterozygous c.899A>G (p.D300G) mutation predicted to alter the coiled-coil domain of lamin A/C. In skin fibroblasts isolated from the proband, the processing and levels of lamin A and C are normal. However, nuclear morphology is aberrant and rescued by treatment with farnesyltransferase inhibitors, as is also the case for HGPS and other laminopathies. Our findings advance knowledge of human LMNA Progeria syndromes, and raise the possibility that typical and atypical Progerias may converge upon a common mechanism to cause premature aging disease.
Kan Cao - One of the best experts on this subject based on the ideXlab platform.
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Mechanisms of genome instability in Hutchinson-Gilford Progeria
Frontiers in Biology, 2017Co-Authors: Haoyue Zhang, Kan CaoAbstract:Background Hutchinson-Gilford Progeria syndrome (HGPS) is a devastating premature aging disorder. It arises from a single point mutation in the LMNA gene. This mutation stimulates an aberrant splicing event and produces progerin, an isoform of the lamin A protein. Accumulation of progerin disrupts numerous physiological pathways and induces defects in nuclear architecture, gene expression, histone modification, cell cycle regulation, mitochondrial functionality, genome integrity and much more. Objective Among these phenotypes, genomic instability is tightly associated with physiological aging and considered a main contributor to the premature aging phenotypes. However, our understanding of the underlying molecular mechanisms of progerin-caused genome instability is far from clear. Results and Conclusion In this review, we summarize some of the recent findings and discuss potential mechanisms through which, progerin affects DNA damage repair and leads to genome integrity.
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Comparing lamin proteins post-translational relative stability using a 2A peptide-based system reveals elevated resistance of progerin to cellular degradation
Nucleus, 2016Co-Authors: Phillip A. Yates, Haoyue Zhang, Kan CaoAbstract:ABSTRACTNuclear lamins are the major components of the nuclear lamina at the periphery of the nucleus, supporting the nuclear envelope and participating in many nuclear processes, including DNA replication, transcription and chromatin organization. A group of diseases, the laminopathies, is associated with mutations in lamin genes. One of the most striking cases is Hutchinson-Gilford Progeria syndrome (HGPS) which is the consequence of a lamin A dominant negative mutant named progerin. Due to the abnormal presence of a permanent C-terminal farnesyl tail, progerin gradually accumulates on the nuclear membrane, perturbing a diversity of signalings and transcriptional events. The accumulation of progerin has led to the speculation that progerin possesses higher stability than the wild type lamin A protein. However, the low solubility of lamin proteins renders traditional immunoprecipitation-dependent methods such as pulse-chase analysis ineffective for comparing the relative stabilities of mutant and wild ty...
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mechanisms controlling the smooth muscle cell death in Progeria via down regulation of poly adp ribose polymerase 1
Proceedings of the National Academy of Sciences of the United States of America, 2014Co-Authors: Haoyue Zhang, Zhengmei Xiong, Kan CaoAbstract:Hutchinson–Gilford Progeria syndrome (HGPS) is a severe human premature aging disorder caused by a lamin A mutant named progerin. Death occurs at a mean age of 13 y from cardiovascular problems. Previous studies revealed loss of vascular smooth muscle cells (SMCs) in the media of large arteries in a patient with HGPS and two mouse models, suggesting a causal connection between the SMC loss and cardiovascular malfunction. However, the mechanisms of how progerin leads to massive SMC loss are unknown. In this study, using SMCs differentiated from HGPS induced pluripotent stem cells, we show that HGPS SMCs exhibit a profound proliferative defect, which is primarily caused by caspase-independent cell death. Importantly, progerin accumulation stimulates a powerful suppression of PARP1 and consequently triggers an activation of the error-prone nonhomologous end joining response. As a result, most HGPS SMCs exhibit prolonged mitosis and die of mitotic catastrophe. This study demonstrates a critical role of PARP1 in mediating SMC loss in patients with HGPS and elucidates a molecular pathway underlying the progressive SMC loss in Progeria.
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Rapamycin Reverses Cellular Phenotypes and Enhances Mutant Protein Clearance in Hutchinson-Gilford Progeria Syndrome Cells
Science Translational Medicine, 2011Co-Authors: Kan Cao, Cecilia D. Blair, Michael R. Erdos, John J. Graziotto, Joseph R. Mazzulli, Dimitri Krainc, Francis S. CollinsAbstract:Hutchinson-Gilford Progeria syndrome (HGPS) is a lethal genetic disorder characterized by premature aging. HGPS is most commonly caused by a de novo single-nucleotide substitution in the lamin A/C gene (LMNA) that partially activates a cryptic splice donor site in exon 11, producing an abnormal lamin A protein termed progerin. Accumulation of progerin in dividing cells adversely affects the integrity of the nuclear scaffold and leads to nuclear blebbing in cultured cells. Progerin is also produced in normal cells, increasing in abundance as senescence approaches. Here, we report the effect of rapamycin, a macrolide antibiotic that has been implicated in slowing cellular and organismal aging, on the cellular phenotypes of HGPS fibroblasts. Treatment with rapamycin abolished nuclear blebbing, delayed the onset of cellular senescence, and enhanced the degradation of progerin in HGPS cells. Rapamycin also decreased the formation of insoluble progerin aggregates and induced clearance through autophagic mechanisms in normal fibroblasts. Our findings suggest an additional mechanism for the beneficial effects of rapamycin on longevity and encourage the hypothesis that rapamycin treatment could provide clinical benefit for children with HGPS.
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Progerin and telomere dysfunction collaborate to trigger cellular senescence in normal human fibroblasts
Journal of Clinical Investigation, 2011Co-Authors: Kan Cao, Cecilia D. Blair, Dina A. Faddah, Julia E. Kieckhaefer, Michael R. Erdos, Michelle Olive, Elizabeth G. Nabel, Francis S. CollinsAbstract:Hutchinson-Gilford Progeria syndrome (HGPS), a devastating premature aging disease, is caused by a point mutation in the lamin A gene (LMNA). This mutation constitutively activates a cryptic splice donor site, resulting in a mutant lamin A protein known as progerin. Recent studies have demonstrated that progerin is also produced at low levels in normal human cells and tissues. However, the cause-and-effect relationship between normal aging and progerin production in normal individuals has not yet been determined. In this study, we have shown in normal human fibroblasts that progressive telomere damage during cellular senescence plays a causative role in activating progerin production. Progressive telomere damage was also found to lead to extensive changes in alternative splicing in multiple other genes. Interestingly, elevated progerin production was not seen during cellular senescence that does not entail telomere shortening. Taken together, our results suggest a synergistic relationship between telomere dysfunction and progerin production during the induction of cell senescence, providing mechanistic insight into how progerin may participate in the normal aging process.
Francis S. Collins - One of the best experts on this subject based on the ideXlab platform.
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Rapamycin Reverses Cellular Phenotypes and Enhances Mutant Protein Clearance in Hutchinson-Gilford Progeria Syndrome Cells
Science Translational Medicine, 2011Co-Authors: Kan Cao, Cecilia D. Blair, Michael R. Erdos, John J. Graziotto, Joseph R. Mazzulli, Dimitri Krainc, Francis S. CollinsAbstract:Hutchinson-Gilford Progeria syndrome (HGPS) is a lethal genetic disorder characterized by premature aging. HGPS is most commonly caused by a de novo single-nucleotide substitution in the lamin A/C gene (LMNA) that partially activates a cryptic splice donor site in exon 11, producing an abnormal lamin A protein termed progerin. Accumulation of progerin in dividing cells adversely affects the integrity of the nuclear scaffold and leads to nuclear blebbing in cultured cells. Progerin is also produced in normal cells, increasing in abundance as senescence approaches. Here, we report the effect of rapamycin, a macrolide antibiotic that has been implicated in slowing cellular and organismal aging, on the cellular phenotypes of HGPS fibroblasts. Treatment with rapamycin abolished nuclear blebbing, delayed the onset of cellular senescence, and enhanced the degradation of progerin in HGPS cells. Rapamycin also decreased the formation of insoluble progerin aggregates and induced clearance through autophagic mechanisms in normal fibroblasts. Our findings suggest an additional mechanism for the beneficial effects of rapamycin on longevity and encourage the hypothesis that rapamycin treatment could provide clinical benefit for children with HGPS.
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Progerin and telomere dysfunction collaborate to trigger cellular senescence in normal human fibroblasts
Journal of Clinical Investigation, 2011Co-Authors: Kan Cao, Cecilia D. Blair, Dina A. Faddah, Julia E. Kieckhaefer, Michael R. Erdos, Michelle Olive, Elizabeth G. Nabel, Francis S. CollinsAbstract:Hutchinson-Gilford Progeria syndrome (HGPS), a devastating premature aging disease, is caused by a point mutation in the lamin A gene (LMNA). This mutation constitutively activates a cryptic splice donor site, resulting in a mutant lamin A protein known as progerin. Recent studies have demonstrated that progerin is also produced at low levels in normal human cells and tissues. However, the cause-and-effect relationship between normal aging and progerin production in normal individuals has not yet been determined. In this study, we have shown in normal human fibroblasts that progressive telomere damage during cellular senescence plays a causative role in activating progerin production. Progressive telomere damage was also found to lead to extensive changes in alternative splicing in multiple other genes. Interestingly, elevated progerin production was not seen during cellular senescence that does not entail telomere shortening. Taken together, our results suggest a synergistic relationship between telomere dysfunction and progerin production during the induction of cell senescence, providing mechanistic insight into how progerin may participate in the normal aging process.
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a lamin a protein isoform overexpressed in hutchinson gilford Progeria syndrome interferes with mitosis in Progeria and normal cells
Proceedings of the National Academy of Sciences of the United States of America, 2007Co-Authors: Ka Cao, Michael R. Erdos, Karima Djabali, Ia C Capell, Francis S. CollinsAbstract:Hutchinson–Gilford Progeria syndrome (HGPS) is a rare genetic disorder characterized by dramatic premature aging. Classic HGPS is caused by a de novo point mutation in exon 11 (residue 1824, C → T) of the LMNA gene, activating a cryptic splice donor and resulting in a mutant lamin A (LA) protein termed “progerin/LAΔ50” that lacks the normal cleavage site to remove a C-terminal farnesyl group. During interphase, irreversibly farnesylated progerin/LAΔ50 anchors to the nuclear membrane and causes characteristic nuclear blebbing. Progerin/LAΔ50's localization and behavior during mitosis, however, are completely unknown. Here, we report that progerin/LAΔ50 mislocalizes into insoluble cytoplasmic aggregates and membranes during mitosis and causes abnormal chromosome segregation and binucleation. These phenotypes are largely rescued with either farnesyltransferase inhibitors or a farnesylation-incompetent mutant progerin/LAΔ50. Furthermore, we demonstrate that small amounts of progerin/LAΔ50 exist in normal fibroblasts, and a significant percentage of these progerin/LAΔ50-expressing normal cells are binucleated, implicating progerin/LAΔ50 as causing similar mitotic defects in the normal aging process. Our findings present evidence of mitotic abnormality in HGPS and may shed light on the general phenomenon of aging.
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A lamin A protein isoform overexpressed in Hutchinson-Gilford Progeria syndrome interferes with mitosis in Progeria and normal cells.
Proceedings of the National Academy of Sciences, 2007Co-Authors: Kan Cao, Michael R. Erdos, Karima Djabali, Brian C. Capell, Francis S. CollinsAbstract:Hutchinson-Gilford Progeria syndrome (HGPS) is a rare genetic disorder characterized by dramatic premature aging. Classic HGPS is caused by a de novo point mutation in exon 11 (residue 1824, C --> T) of the LMNA gene, activating a cryptic splice donor and resulting in a mutant lamin A (LA) protein termed "progerin/LADelta50" that lacks the normal cleavage site to remove a C-terminal farnesyl group. During interphase, irreversibly farnesylated progerin/LADelta50 anchors to the nuclear membrane and causes characteristic nuclear blebbing. Progerin/LADelta50's localization and behavior during mitosis, however, are completely unknown. Here, we report that progerin/LADelta50 mislocalizes into insoluble cytoplasmic aggregates and membranes during mitosis and causes abnormal chromosome segregation and binucleation. These phenotypes are largely rescued with either farnesyltransferase inhibitors or a farnesylation-incompetent mutant progerin/LADelta50. Furthermore, we demonstrate that small amounts of progerin/LADelta50 exist in normal fibroblasts, and a significant percentage of these progerin/LADelta50-expressing normal cells are binucleated, implicating progerin/LADelta50 as causing similar mitotic defects in the normal aging process. Our findings present evidence of mitotic abnormality in HGPS and may shed light on the general phenomenon of aging.
Vicente Andrés - One of the best experts on this subject based on the ideXlab platform.
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Vascular Smooth Muscle Cell-Specific Progerin Expression Provokes Contractile Impairment in a Mouse Model of Hutchinson-Gilford Progeria Syndrome that Is Ameliorated by Nitrite Treatment
Cells, 2020Co-Authors: Lara Del Campo, Amanda Sánchez-lópez, Cristina González-gómez, María J. Andrés-manzano, Beatriz Dorado, Vicente AndrésAbstract:Cardiovascular disease (CVD) is the main cause of death worldwide, and aging is its leading risk factor. Aging is much accelerated in Hutchinson-Gilford Progeria syndrome (HGPS), an ultra-rare genetic disorder provoked by the ubiquitous expression of a mutant protein called progerin. HGPS patients die in their teens, primarily due to cardiovascular complications. The primary causes of age-associated CVD are endothelial dysfunction and dysregulated vascular tone; however, their contribution to progerin-induced CVD remains poorly characterized. In the present study, we found that progeroid LmnaG609G/G609G mice with ubiquitous progerin expression show both endothelial dysfunction and severe contractile impairment. To assess the relative contribution of specific vascular cell types to these anomalies, we examined LmnaLCS/LCSTie2Cretg/+ and LmnaLCS/LCSSm22αCretg/+ mice, which express progerin specifically in endothelial cells (ECs) and vascular smooth muscle cells (VSMCs), respectively. Whereas vessel contraction was impaired in mice with VSMC-specific progerin expression, we observed no endothelial dysfunction in mice with progerin expression restricted to VSMCs or ECs. Vascular tone regulation in progeroid mice was ameliorated by dietary sodium nitrite supplementation. Our results identify VSMCs as the main cell type causing contractile impairment in a mouse model of HGPS that is ameliorated by nitrite treatment.
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aging in the cardiovascular system lessons from hutchinson gilford Progeria syndrome
Annual Review of Physiology, 2018Co-Authors: Magda R Hamczyk, Lara Del Campo, Vicente AndrésAbstract: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. Progerin causes extensive atherosclerosis and cardiac electrophysiological alterations that invariably lead to premature aging and death. This review summarizes the main structural and functional alterations to the cardiovascular system during physiological and premature aging and discusses the mechanisms underlying exaggerated CVD and aging induced by prelamin A and progerin. Because both proteins are expressed in normally aging non-HGPS individuals, and most hallmarks of normal aging occur in Progeria, research on HGPS can identify mechanisms underlying physiological aging.
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defective extracellular pyrophosphate metabolism promotes vascular calcification in a mouse model of hutchinson gilford Progeria syndrome that is ameliorated on pyrophosphate treatment
Circulation, 2013Co-Authors: Ricardo Villabellosta, Fernando G. Osorio, Carlos Lopezotin, Jose Riveratorres, Rebeca Acinperez, Jose Antonio Enriquez, Vicente AndrésAbstract:Background—Progerin is a mutant form of lamin A responsible for Hutchinson-Gilford Progeria syndrome (HGPS), a premature aging disorder characterized by excessive atherosclerosis and vascular calcification that leads to premature death, predominantly of myocardial infarction or stroke. The goal of this study was to investigate mechanisms that cause excessive vascular calcification in HGPS. Methods and Results—We performed expression and functional studies in wild-type mice and knock-in LmnaG609G/+ mice expressing progerin, which mimic the main clinical manifestations of HGPS. LmnaG609G/+ mice showed excessive aortic calcification, and primary aortic vascular smooth muscle cells from these progeroid animals had an impaired capacity to inhibit vascular calcification. This defect in progerin-expressing vascular smooth muscle cells is associated with increased expression and activity of tissue-nonspecific alkaline phosphatase and mitochondrial dysfunction, which leads to reduced ATP synthesis. Accordingly, Lm...
