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1.
Int J Mol Sci ; 23(19)2022 Oct 03.
Artículo en Inglés | MEDLINE | ID: mdl-36233036

RESUMEN

Hutchinson-Gilford progeria syndrome (HGPS) is a rare fatal disorder characterized by premature aging and death at a median age of 14.5 years. The most common cause of HGPS (affecting circa 90% of patients) is a de novo heterozygous synonymous single-base substitution (c.1824C>T; p.G608G) in the LMNA gene that results in the accumulation of progerin, an aberrant form of lamin A that, unlike mature lamin A, remains permanently farnesylated. The ratio of progerin to mature lamin A correlates with disease severity in HGPS patients, and can be used to assess the effectiveness of therapies aimed at lessening aberrant splicing or progerin farnesylation. We recently showed that the endogenous content of lamin A and progerin can be measured by mass spectrometry (MS), providing an alternative to immunological methods, which lack the necessary specificity and quantitative accuracy. Here, we present the first non-immunological method that reliably quantifies the levels of wild-type lamin A and farnesylated progerin in cells from HGPS patients. This method, which is based on a targeted MS approach and the use of isotope-labeled internal standards, could be applied in ongoing clinical trials evaluating the efficacy of drugs that inhibit progerin farnesylation.


Asunto(s)
Progeria , Adolescente , Línea Celular , Núcleo Celular , Humanos , Lamina Tipo A/genética , Espectrometría de Masas , Progeria/genética
2.
Int J Mol Sci ; 22(16)2021 Aug 06.
Artículo en Inglés | MEDLINE | ID: mdl-34445154

RESUMEN

The continuous relationship between blood pressure (BP) and cardiovascular events makes the distinction between elevated BP and hypertension based on arbitrary cut-off values for BP. Even mild BP elevations manifesting as high-normal BP have been associated with cardiovascular risk. We hypothesize that persistent elevated BP increases atherosclerotic plaque development. To evaluate this causal link, we developed a new mouse model of elevated BP based on adeno-associated virus (AAV) gene transfer. We constructed AAV vectors to support transfer of the hRenin and hAngiotensinogen genes. A single injection of AAV-Ren/Ang (1011 total viral particles) induced sustained systolic BP increase (130 ± 20 mmHg, vs. 110 ± 15 mmHg in controls; p = 0.05). In ApoE-/- mice, AAV-induced mild BP elevation caused larger atherosclerotic lesions evaluated by histology (10-fold increase vs. normotensive controls). In this preclinical model, atheroma plaques development was attenuated by BP control with a calcium channel blocker, indicating that a small increase in BP within a physiological range has a substantial impact on plaque development in a preclinical model of atherosclerosis. These data support that non-optimal BP represents a risk for atherosclerosis development. Earlier intervention in elevated BP may prevent or delay morbidity and mortality associated with atherosclerosis.


Asunto(s)
Aterosclerosis/etiología , Presión Sanguínea , Hipertensión/complicaciones , Animales , Aterosclerosis/fisiopatología , Modelos Animales de Enfermedad , Humanos , Hipertensión/fisiopatología , Masculino , Ratones Endogámicos C57BL
3.
Proc Natl Acad Sci U S A ; 113(46): E7250-E7259, 2016 11 15.
Artículo en Inglés | MEDLINE | ID: mdl-27799555

RESUMEN

Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disease caused by defective prelamin A processing, leading to nuclear lamina alterations, severe cardiovascular pathology, and premature death. Prelamin A alterations also occur in physiological aging. It remains unknown how defective prelamin A processing affects the cardiac rhythm. We show age-dependent cardiac repolarization abnormalities in HGPS patients that are also present in the Zmpste24-/- mouse model of HGPS. Challenge of Zmpste24-/- mice with the ß-adrenergic agonist isoproterenol did not trigger ventricular arrhythmia but caused bradycardia-related premature ventricular complexes and slow-rate polymorphic ventricular rhythms during recovery. Patch-clamping in Zmpste24-/- cardiomyocytes revealed prolonged calcium-transient duration and reduced sarcoplasmic reticulum calcium loading and release, consistent with the absence of isoproterenol-induced ventricular arrhythmia. Zmpste24-/- progeroid mice also developed severe fibrosis-unrelated bradycardia and PQ interval and QRS complex prolongation. These conduction defects were accompanied by overt mislocalization of the gap junction protein connexin43 (Cx43). Remarkably, Cx43 mislocalization was also evident in autopsied left ventricle tissue from HGPS patients, suggesting intercellular connectivity alterations at late stages of the disease. The similarities between HGPS patients and progeroid mice reported here strongly suggest that defective cardiac repolarization and cardiomyocyte connectivity are important abnormalities in the HGPS pathogenesis that increase the risk of arrhythmia and premature death.


Asunto(s)
Arritmias Cardíacas/fisiopatología , Trastorno del Sistema de Conducción Cardíaco/fisiopatología , Progeria/fisiopatología , Adolescente , Adulto , Animales , Arritmias Cardíacas/metabolismo , Calcio/fisiología , Trastorno del Sistema de Conducción Cardíaco/metabolismo , Niño , Preescolar , Conexina 43/metabolismo , Conexina 43/fisiología , Femenino , Corazón/fisiología , Humanos , Masculino , Proteínas de la Membrana/genética , Proteínas de la Membrana/fisiología , Metaloendopeptidasas/genética , Metaloendopeptidasas/fisiología , Ratones Endogámicos C57BL , Ratones Noqueados , Miocardio/metabolismo , Lámina Nuclear/fisiología , Progeria/metabolismo , Retículo Sarcoplasmático/fisiología , Adulto Joven
4.
Circulation ; 127(24): 2442-51, 2013 Jun 18.
Artículo en Inglés | MEDLINE | ID: mdl-23690466

RESUMEN

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 Lmna(G609G/+) mice expressing progerin, which mimic the main clinical manifestations of HGPS. Lmna(G609G/+) 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, Lmna(G609G/+) vascular smooth muscle cells are defective for the production and extracellular accumulation of pyrophosphate, a major inhibitor of vascular calcification. We also found increased alkaline phosphatase activity and reduced ATP and pyrophosphate levels in plasma of Lmna(G609G/+) mice without changes in phosphorus and calcium. Treatment with pyrophosphate inhibited vascular calcification in progeroid mice. CONCLUSIONS: Excessive vascular calcification in Lmna(G609G) mice is caused by reduced extracellular accumulation of pyrophosphate that results from increased tissue-nonspecific alkaline phosphatase activity and diminished ATP availability caused by mitochondrial dysfunction in vascular smooth muscle cells. Excessive calcification is ameliorated on pyrophosphate treatment. These findings reveal a previously undefined pathogenic process in HGPS that may also contribute to vascular calcification in normal aging, because progerin progressively accumulates in the vascular tissue of individuals without HGPS.


Asunto(s)
Difosfatos/metabolismo , Difosfatos/uso terapéutico , Progeria/tratamiento farmacológico , Progeria/metabolismo , Calcificación Vascular/tratamiento farmacológico , Calcificación Vascular/metabolismo , Adenosina Trifosfato/metabolismo , Fosfatasa Alcalina/metabolismo , Animales , Aorta/efectos de los fármacos , Aorta/metabolismo , Aorta/patología , Células Cultivadas , Difosfatos/farmacología , Modelos Animales de Enfermedad , Lamina Tipo A/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Mutantes , Mitocondrias Musculares/fisiología , Músculo Liso Vascular/efectos de los fármacos , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patología , Resultado del Tratamiento
5.
J Clin Med ; 12(2)2023 Jan 06.
Artículo en Inglés | MEDLINE | ID: mdl-36675416

RESUMEN

Here, we present a review focusing on three relevant issues related to COVID-19 and its impact in older adults (60 years and older). SARS-CoV-2 infection starts in the respiratory system, but the development of systemic diseases accompanied by severe clinical manifestations has also been reported, with cardiovascular and immune system dysfunction being the major ones. Additionally, the presence of comorbidities and aging represent major risk factors for the severity and poor prognosis of the disease. Since aging-associated decline has been largely related to immune and cardiovascular alterations, we sought to investigate the consequences and the underlying mechanisms of these pathologies to understand the severity of the illness in this population. Understanding the effects of COVID-19 on both systems should translate into comprehensive and improved medical care for elderly COVID-19 patients, preventing cardiovascular as well as immunological alterations in this population. Approved therapies that contribute to the improvement of symptoms and a reduction in mortality, as well as new therapies in development, constitute an approach to managing these disorders. Among them, we describe antivirals, cytokine antagonists, cytokine signaling pathway inhibitors, and vaccines.

6.
Pharmaceutics ; 13(3)2021 Mar 08.
Artículo en Inglés | MEDLINE | ID: mdl-33800318

RESUMEN

Selenium nanoparticles (SeNPs) have been receiving special attention in recent years due to their antioxidant capacity and antitumor properties. However, the mechanisms associated with these properties remain to be elucidated. For this reason, a global transcriptome analysis has been designed in this work and it was carried out using human hepatocarcinoma cells and chitosan-stabilized SeNPs (Ch-SeNPs) to identify new targets and pathways related to the antitumor mechanisms associated with Ch-SeNPs. The results obtained confirm the alteration of the cell cycle and the effect of Ch-SeNPs on different tumor suppressors and other molecules involved in key mechanisms related to cancer progression. Furthermore, we demonstrated the antioxidant properties of these nanoparticles and their capacity to induce senescence, which was further confirmed through the measurement of ß-galactosidase activity.

7.
Aging Cell ; 19(9): e13203, 2020 09.
Artículo en Inglés | MEDLINE | ID: mdl-32729659

RESUMEN

Aging is the main risk factor for cardiovascular and metabolic diseases, which have become a global concern as the world population ages. These diseases and the aging process are exacerbated in Hutchinson-Gilford progeria syndrome (HGPS or progeria). Here, we evaluated the cardiometabolic disease in animal models of premature and normal aging with the aim of identifying alterations that are shared or specific to each condition. Despite differences in body composition and metabolic markers, prematurely and normally aging mice developed heart failure and similar cardiac electrical abnormalities. High-throughput proteomics of the hearts of progeric and normally aged mice revealed altered protein oxidation and glycation, as well as dysregulated pathways regulating energy metabolism, proteostasis, gene expression, and cardiac muscle contraction. These results were corroborated in the hearts of progeric pigs, underscoring the translational potential of our findings, which could help in the design of strategies to prevent or slow age-related cardiometabolic disease.


Asunto(s)
Enfermedades Cardiovasculares/fisiopatología , Progeria/fisiopatología , Proteómica/métodos , Envejecimiento , Animales , Modelos Animales de Enfermedad , Humanos , Ratones , Porcinos
8.
J Clin Med ; 10(1)2020 Dec 25.
Artículo en Inglés | MEDLINE | ID: mdl-33375572

RESUMEN

BCR-ABL is an aberrant tyrosine kinase responsible for chronic myeloid leukemia (CML). Tyrosine kinase inhibitors (TKIs) induce a potent antileukemic response mostly based on the inhibition of BCR-ABL, but they also increase the activity of Natural Killer (NK) and CD8+ T cells. After several years, patients may interrupt treatment due to sustained, deep molecular response. By unknown reasons, half of the patients relapse during treatment interruption, whereas others maintain a potent control of the residual leukemic cells for several years. In this study, several immunological parameters related to sustained antileukemic control were analyzed. According to our results, the features more related to poor antileukemic control were as follows: low levels of cytotoxic cells such as NK, (Natural Killer T) NKT and CD8±TCRγß+ T cells; low expression of activating receptors on the surface of NK and NKT cells; impaired synthesis of proinflammatory cytokines or proteases from NK cells; and HLA-E*0103 homozygosis and KIR haplotype BX. A Random Forest algorithm predicted 90% of the accuracy for the classification of CML patients in groups of relapse or non-relapse according to these parameters. Consequently, these features may be useful as biomarkers predictive of CML relapse in patients that are candidates to initiate treatment discontinuation.

9.
Front Pharmacol ; 10: 1011, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31619990

RESUMEN

Deregulated activity of the Src tyrosine kinases leads to malignant transformation. Since the FDA approval of the tyrosine kinase inhibitor, imatinib, in 2001 for the treatment of chronic myeloid leukemia (CML), the number of these inhibitors together with Src tyrosine kinase inhibitors (STKIs) has increased notably due to their beneficial effects. Dasatinib, a second-generation STKI inhibitor widely studied, proved high efficiency in CML patients resistant to imatinib. In the last decade STKIs have also been implicated and showed therapeutic potential for the treatment of diverse pathologies other than cancer. In this regard, we review the properties of STKIs, dasatinib in particular, including its immunomodulatory role. Similarly, the potential benefits, adverse effects, and safety concerns of these inhibitors regarding viral infections are considered. Moreover, since life expectancy has increased in the last decades accompanied by age-related morbidity, the reduction of undesirable effects associated to aging has become a powerful therapeutic target. Here, we comment on the ability of STKIs to alleviate age-associated physical dysfunction and their potential impact in the clinic.

10.
Cell Stem Cell ; 25(3): 407-418.e6, 2019 09 05.
Artículo en Inglés | MEDLINE | ID: mdl-31303548

RESUMEN

Hematopoietic stem cells (HSCs) residing in the bone marrow (BM) accumulate during aging but are functionally impaired. However, the role of HSC-intrinsic and -extrinsic aging mechanisms remains debated. Megakaryocytes promote quiescence of neighboring HSCs. Nonetheless, whether megakaryocyte-HSC interactions change during pathological/natural aging is unclear. Premature aging in Hutchinson-Gilford progeria syndrome recapitulates physiological aging features, but whether these arise from altered stem or niche cells is unknown. Here, we show that the BM microenvironment promotes myelopoiesis in premature/physiological aging. During physiological aging, HSC-supporting niches decrease near bone but expand further from bone. Increased BM noradrenergic innervation promotes ß2-adrenergic-receptor(AR)-interleukin-6-dependent megakaryopoiesis. Reduced ß3-AR-Nos1 activity correlates with decreased endosteal niches and megakaryocyte apposition to sinusoids. However, chronic treatment of progeroid mice with ß3-AR agonist decreases premature myeloid and HSC expansion and restores the proximal association of HSCs to megakaryocytes. Therefore, normal/premature aging of BM niches promotes myeloid expansion and can be improved by targeting the microenvironment.


Asunto(s)
Envejecimiento Prematuro/patología , Envejecimiento/fisiología , Médula Ósea/fisiología , Células Madre Hematopoyéticas/fisiología , Megacariocitos/fisiología , Células Mieloides/fisiología , Progeria/patología , Agonistas Adrenérgicos/administración & dosificación , Envejecimiento/metabolismo , Envejecimiento Prematuro/metabolismo , Animales , Diferenciación Celular , Encapsulación Celular , Proliferación Celular , Modelos Animales de Enfermedad , Humanos , Interleucina-6/metabolismo , Ratones , Óxido Nítrico Sintasa de Tipo I/metabolismo , Progeria/metabolismo , Receptores Adrenérgicos beta 2/metabolismo , Transducción de Señal , Nicho de Células Madre
11.
Methods Mol Biol ; 1339: 309-22, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-26445798

RESUMEN

Atherosclerosis involves changes in gene and protein expression patterns in affected arteries. Quantification of these alterations is essential for understanding the molecular mechanisms underlying this pathology. Western blot and real-time PCR-used to quantify protein and messenger RNA levels, respectively-are invaluable molecular biology tools, particularly when material is limited. The availability of many genetically modified mouse models of atherosclerosis makes the mouse aorta an ideal tissue in which to carry out these expression pattern analyses. In this chapter, protocols are presented for mRNA and protein extraction from mouse aorta and for the accurate quantification of mRNA expression by RT-PCR and of proteins by western blot.


Asunto(s)
Aorta/metabolismo , Enfermedades de la Aorta/genética , Enfermedades de la Aorta/metabolismo , Aterosclerosis/genética , Aterosclerosis/metabolismo , Western Blotting/métodos , Reacción en Cadena en Tiempo Real de la Polimerasa/métodos , Animales , Modelos Animales de Enfermedad , Regulación de la Expresión Génica , Marcadores Genéticos , Ratones , ARN Mensajero/genética , ARN Mensajero/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Factores de Tiempo
12.
J Hypertens ; 33(4): 843-50; discussion 850, 2015 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-25915889

RESUMEN

OBJECTIVE: The Notch pathway has been linked to pulmonary hypertension, but its role in systemic hypertension and, in particular in left ventricular hypertrophy (LVH), remains poorly understood. The main objective of this work was to analyse the effect of inhibiting the Notch pathway on the establishment and maintenance of angiotensin II (Ang-II)-induced arterial hypertension and LVH in adult mice with inducible genetic deletion of γ-secretase, and to test preclinically the therapeutic efficacy of γ-secretase inhibitors (GSIs). BASIC METHODS: We analysed Ang-II responses in primary cultures of vascular smooth muscle cells obtained from a novel mouse model with inducible genetic deletion of the γ-secretase complex, and the effects of GSI treatment on a mouse cardiac cell line. We also investigated Ang-II-induced hypertension and LVH in our novel mouse strain lacking the γ-secretase complex and in GSI-treated wild-type mice. Moreover, we analysed vascular tissue from hypertensive patients with and without LVH. MAIN RESULTS: Vascular smooth muscle cells activate the Notch pathway in response to Ang-II both 'in vitro' and 'in vivo'. Genetic deletion of γ-secretase in adult mice prevented Ang-II-induced hypertension and LVH without causing major adverse effects. Treatment with GSI reduced Ang-II-induced hypertrophy of a cardiac cell line 'in vitro' and LVH in wild-type mice challenged with Ang-II. We also report elevated expression of the Notch target HES5 in vascular tissue from hypertensive patients with LVH compared with those without LVH. CONCLUSION: The Notch pathway is activated in the vasculature of mice with hypertension and LVH, and its inhibition via inducible genetic γ-secretase deletion protects against both conditions. Preliminary observations in hypertensive patients with LVH support the translational potential of these findings. Moreover, GSI treatment protects wild-type mice from Ang-II-induced LVH without affecting blood pressure. Our results unveil the potential use of GSIs in the treatment of hypertensive patients with LVH.


Asunto(s)
Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Cardiomegalia/prevención & control , Dibenzazepinas/uso terapéutico , Hipertensión/prevención & control , Hipertrofia Ventricular Izquierda/prevención & control , Angiotensina II , Animales , Presión Sanguínea/efectos de los fármacos , Células Cultivadas , Dibenzazepinas/farmacología , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Humanos , Hipertensión/inducido químicamente , Masculino , Ratones , Persona de Mediana Edad , Músculo Liso Vascular/efectos de los fármacos , Músculo Liso Vascular/metabolismo , Transducción de Señal/efectos de los fármacos
13.
J Mol Biol ; 426(3): 674-90, 2014 Feb 06.
Artículo en Inglés | MEDLINE | ID: mdl-24239949

RESUMEN

TAX1BP1 is a novel ubiquitin-binding adaptor protein involved in the negative regulation of the NF-kappaB transcription factor, which is a key player in inflammatory responses, immunity and tumorigenesis. TAX1BP1 recruits A20 to the ubiquitinated signaling proteins TRAF6 and RIP1, leading to their A20-mediated deubiquitination and the disruption of IL-1-induced and TNF-induced NF-kappaB signaling, respectively. The two zinc fingers localized at its C-terminus function as novel ubiquitin-binding domains (UBZ, ubiquitin-binding zinc finger). Here we present for the first time both the solution and crystal structures of two classical UBZ domains in tandem within the human TAX1BP1. The relative orientation of the two domains is slightly different in the X-ray structure with respect to the NMR structure, indicating some degree of conformational flexibility, which is rationalized by NMR relaxation data. The observed degree of flexibility and stability between the two UBZ domains might have consequences on the recognition mechanism of interacting partners.


Asunto(s)
Péptidos y Proteínas de Señalización Intracelular/química , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Proteínas de Neoplasias/química , Proteínas de Neoplasias/metabolismo , Ubiquitina/metabolismo , Secuencias de Aminoácidos , Secuencia de Aminoácidos , Cristalografía por Rayos X , Humanos , Espectroscopía de Resonancia Magnética , Datos de Secuencia Molecular , Unión Proteica , Estructura Terciaria de Proteína , Dispersión del Ángulo Pequeño , Homología de Secuencia de Aminoácido , Transducción de Señal
14.
PLoS One ; 9(4): e93074, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-24691161

RESUMEN

Polµ is an error-prone PolX polymerase that contributes to classical NHEJ DNA repair. Mice lacking Polµ (Polµ(-/-)) show altered hematopoiesis homeostasis and DSB repair and a more pronounced nucleolytic resection of some V(D)J junctions. We previously showed that Polµ(-/-) mice have increased learning capacity at old ages, suggesting delayed brain aging. Here we investigated the effect of Polµ(-/-) deficiency on liver aging. We found that old Polµ(-/-) mice (>20 month) have greater liver regenerative capacity compared with wt animals. Old Polµ(-/-) liver showed reduced genomic instability and increased apoptosis resistance. However, Polµ(-/-) mice did not show an extended life span and other organs (e.g., heart) aged normally. Our results suggest that Polµ deficiency activates transcriptional networks that reduce constitutive apoptosis, leading to enhanced liver repair at old age.


Asunto(s)
Envejecimiento/patología , ADN Polimerasa Dirigida por ADN/deficiencia , Hígado/patología , Estrés Oxidativo , Animales , Inestabilidad Genómica , Hígado/fisiopatología , Pruebas de Función Hepática , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Modelos Biológicos , Miocardio/patología , Fenotipo , Intercambio de Cromátides Hermanas
15.
J Proteomics ; 91: 466-77, 2013 Oct 08.
Artículo en Inglés | MEDLINE | ID: mdl-23969228

RESUMEN

Hutchinson-Gilford progeria syndrome (HGPS) is a rare segmental premature aging disorder that recapitulates some biological and physical aspects of physiological aging. The disease is caused by a sporadic dominant mutation in the LMNA gene that leads to the expression of progerin, a mutant form of lamin A that lacks 50 amino acids and retains a toxic farnesyl modification in its carboxy-terminus. However, the mechanisms underlying cellular damage and senescence and accelerated aging in HGPS are incompletely understood. Here, we analyzed fibroblasts from healthy subjects and HGPS patients using SILAC (stable isotope labeling with amino acids in cell culture). We found in HGPS cells a marked downregulation of mitochondrial oxidative phosphorylation proteins accompanied by mitochondrial dysfunction, a process thought to provoke broad organ decline during normal aging. We also found mitochondrial dysfunction in fibroblasts from adult progeroid mice expressing progerin (Lmna(G609G/G609G) knock-in mice) or prelamin A (Zmpste24-null mice). Analysis of tissues from these mouse models revealed that the damaging effect of these proteins on mitochondrial function is time- and dose-dependent. Mitochondrial alterations were not observed in the brain, a tissue with extremely low progerin expression that seems to be unaffected in HGPS. Remarkably, mitochondrial function was restored in progeroid mouse fibroblasts treated with the isoprenylation inhibitors FTI-277 or pravastatin plus zoledronate, which are being tested in HGPS clinical trials. Our results suggest that mitochondrial dysfunction contributes to premature organ decline and aging in HGPS. Beyond its effects on progeria, prelamin A and progerin may also contribute to mitochondrial dysfunction and organ damage during normal aging, since these proteins are expressed in cells and tissues from non-HGPS individuals, most prominently at advanced ages. BIOLOGICAL SIGNIFICANCE: Mutations in LMNA or defective processing of prelamin A causes premature aging disorders, including Hutchinson-Gilford progeria syndrome (HGPS). Most HGPS patients carry in heterozygosis a de-novo point mutation (c.1824C>T: GGC>GGT; p.G608G) which causes the expression of the lamin A mutant protein called progerin. Despite the importance of progerin and prelamin A in accelerated aging, the underlying molecular mechanisms remain largely unknown. To tackle this question, we compared the proteome of skin-derived dermal fibroblast from HGPS patients and age-matched controls using quantitative stable isotope labeling with amino acids in cell culture (SILAC). Our results show a pronounced down-regulation of several components of the mitochondrial ATPase complex accompanied by up-regulation of some glycolytic enzymes. Accordingly, functional studies demonstrated mitochondrial dysfunction in HGPS fibroblasts. Moreover, our expression and functional studies using cellular and animal models confirmed that mitochondrial dysfunction is a feature of progeria which develops in a time- and dose-dependent manner. Finally, we demonstrate improved mitochondrial function in progeroid mouse cells treated with a combination of statins and aminobisphosphonates, two drugs that are being evaluated in ongoing HGPS clinical trials. Although further studies are needed to unravel the mechanisms through which progerin and prelamin A provoke mitochondrial abnormalities, our findings may pave the way to improved treatments of HGPS. These studies may also improve our knowledge of the mechanisms leading to mitochondrial dysfunction during normal aging, since both progerin and prelamin A have been found to accumulate during normal aging.


Asunto(s)
Aminoácidos/química , Regulación de la Expresión Génica , Mitocondrias/metabolismo , Progeria/metabolismo , Adenosina Trifosfato/química , Adolescente , Animales , Niño , Difosfonatos/química , Femenino , Fibroblastos/metabolismo , Galactosa/metabolismo , Glucosa/química , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/química , Imidazoles/química , Lamina Tipo A , Masculino , Metionina/análogos & derivados , Metionina/química , Ratones , Mitocondrias/patología , Mutación , Proteínas Nucleares/química , Consumo de Oxígeno , Pravastatina/química , Precursores de Proteínas/química , Proteómica , Piel/metabolismo , Ácido Zoledrónico
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