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Aging Mar 2020
Topics: Aging; Humans; Karyopherins; Nuclear Proteins; Progeria; Receptors, Cytoplasmic and Nuclear; Signal Transduction; Exportin 1 Protein
PubMed: 32200356
DOI: 10.18632/aging.102948 -
Aging Cell Sep 2023Hutchinson-Gilford progeria syndrome (HGPS) is a premature aging disorder affecting tissues of mesenchymal origin. Most individuals with HGPS harbor a de novo...
Hutchinson-Gilford progeria syndrome (HGPS) is a premature aging disorder affecting tissues of mesenchymal origin. Most individuals with HGPS harbor a de novo c.1824C > T (p.G608G) mutation in the gene encoding lamin A (LMNA), which activates a cryptic splice donor site resulting in production of the toxic "progerin" protein. Clinical manifestations include growth deficiency, lipodystrophy, sclerotic dermis, cardiovascular defects, and bone dysplasia. Here we utilized the Lmna knock-in (KI) mouse model of HGPS to further define mechanisms of bone loss associated with normal and premature aging disorders. Newborn skeletal staining of KI mice revealed altered rib cage shape and spinal curvature, and delayed calvarial mineralization with increased craniofacial and mandibular cartilage content. MicroCT analysis and mechanical testing of adult femurs indicated increased fragility associated with reduced bone mass, recapitulating the progressive bone deterioration that occurs in HGPS patients. We investigated mechanisms of bone loss in KI mice at the cellular level in bone cell populations. Formation of wild-type and KI osteoclasts from marrow-derived precursors was inhibited by KI osteoblast-conditioned media in vitro, suggesting a secreted factor(s) responsible for decreased osteoclasts on KI trabecular surfaces in vivo. Cultured KI osteoblasts exhibited abnormal differentiation characterized by reduced deposition and mineralization of extracellular matrix with increased lipid accumulation compared to wild-type, providing a mechanism for altered bone formation. Furthermore, quantitative analyses of KI transcripts confirmed upregulation of adipogenic genes both in vitro and in vivo. Thus, osteoblast phenotypic plasticity, inflammation and altered cellular cross-talk contribute to abnormal bone formation in HGPS mice.
Topics: Mice; Animals; Progeria; Aging, Premature; Mutation; Lamin Type A; Cell Differentiation; Bone Diseases, Developmental
PubMed: 37365004
DOI: 10.1111/acel.13903 -
Aging Cell Oct 2023Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disease caused by nuclear envelope alterations that lead to accelerated aging and premature death. Several...
Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disease caused by nuclear envelope alterations that lead to accelerated aging and premature death. Several studies have linked health and longevity to cell-extrinsic mechanisms, highlighting the relevance of circulating factors in the aging process as well as in age-related diseases. We performed a global plasma proteomic analysis in two preclinical progeroid models (Lmna and Zmpste24 mice) using aptamer-based proteomic technology. Pathways related to the extracellular matrix, growth factor response and calcium ion binding were among the most enriched in the proteomic signature of progeroid samples compared to controls. Despite the global downregulation trend found in the plasma proteome of progeroid mice, several proteins associated with cardiovascular disease, the main cause of death in HGPS, were upregulated. We also developed a chronological age predictor using plasma proteome data from a cohort of healthy mice (aged 1-30 months), that reported an age acceleration when applied to progeroid mice, indicating that these mice exhibit an "old" plasma proteomic signature. Furthermore, when compared to naturally-aged mice, a great proportion of differentially expressed circulating proteins in progeroid mice were specific to premature aging, highlighting secretome-associated differences between physiological and accelerated aging. This is the first large-scale profiling of the plasma proteome in progeroid mice, which provides an extensive list of candidate circulating plasma proteins as potential biomarkers and/or therapeutic targets for further exploration and hypothesis generation in the context of both physiological and premature aging.
Topics: Humans; Mice; Animals; Progeria; Aging, Premature; Proteomics; Proteome; Secretome; Lamin Type A
PubMed: 37565451
DOI: 10.1111/acel.13952 -
The Journal of Investigative Dermatology Nov 2015The nuclear lamina, a protein network located under the nuclear membrane, has during the past decade found increasing interest due to its significant involvement in a... (Review)
Review
The nuclear lamina, a protein network located under the nuclear membrane, has during the past decade found increasing interest due to its significant involvement in a range of genetic diseases, including the segmental premature aging syndromes Hutchinson-Gilford progeria syndrome, restrictive dermopathy, and atypical Werner syndrome. In this review we examine these diseases, some caused by mutations in the LMNA gene, and their skin disease features. Advances within this area might also provide novel insights into the biology of skin aging, as recent data suggest that low levels of progerin are expressed in unaffected individuals and these levels increase with aging.
Topics: Adult; Aging, Premature; Animals; Child, Preschool; Female; Genetic Predisposition to Disease; Humans; Lamin Type A; Male; Mice; Mutation; Progeria; Prognosis; Rare Diseases; Severity of Illness Index; Skin Aging; Skin Diseases
PubMed: 26290387
DOI: 10.1038/jid.2015.295 -
Cells Sep 2023Hutchinson-Gilford progeria syndrome (HGPS) is an extremely rare genetic disorder caused by the mutant protein progerin, which is expressed by the abnormal splicing of... (Review)
Review
Hutchinson-Gilford progeria syndrome (HGPS) is an extremely rare genetic disorder caused by the mutant protein progerin, which is expressed by the abnormal splicing of the gene. HGPS affects systemic levels, with the exception of cognition or brain development, in children, showing that cellular aging can occur in the short term. Studying progeria could be useful in unraveling the causes of human aging (as well as fatal age-related disorders). Elucidating the clear cause of HGPS or the development of a therapeutic medicine could improve the quality of life and extend the survival of patients. This review aimed to (i) briefly describe how progerin was discovered as the causative agent of HGPS, (ii) elucidate the puzzling observation of the absence of primary neurological disease in HGPS, (iii) present several studies showing the deleterious effects of progerin and the beneficial effects of its inhibition, and (iv) summarize research to develop a therapy for HGPS and introduce clinical trials for its treatment.
Topics: Child; Humans; Lamin Type A; Progeria; Quality of Life; Medicine; Aging; Rare Diseases
PubMed: 37759521
DOI: 10.3390/cells12182299 -
International Journal of Molecular... Nov 2017Premature aging disorders including Hutchinson-Gilford progeria syndrome (HGPS) and Werner syndrome, are a group of rare monogenic diseases leading to reduced lifespan... (Review)
Review
Premature aging disorders including Hutchinson-Gilford progeria syndrome (HGPS) and Werner syndrome, are a group of rare monogenic diseases leading to reduced lifespan of the patients. Importantly, these disorders mimic several features of physiological aging. Despite the interest on the study of these diseases, the underlying biological mechanisms remain unknown and no treatment is available. Recent studies on HGPS (due to mutations of the gene encoding for the nucleoskeletal proteins lamin A/C) have reported disruptions in cellular and molecular mechanisms modulating genomic stability and stem cell populations, thus giving the nuclear lamina a relevant function in nuclear organization, epigenetic regulation and in the maintenance of the stem cell pool. In this context, modeling premature aging with induced pluripotent stem cells (iPSCs) offers the possibility to study these disorders during self-renewal and differentiation into relevant cell types. iPSCs generated by cellular reprogramming from adult somatic cells allows researchers to understand pathophysiological mechanisms and enables the performance of drug screenings. Moreover, the recent development of precision genome editing offers the possibility to study the complex mechanisms underlying senescence and the possibility to correct disease phenotypes, paving the way for future therapeutic interventions.
Topics: Aging, Premature; Animals; CRISPR-Cas Systems; Cellular Senescence; Epigenesis, Genetic; Humans; Induced Pluripotent Stem Cells; Lamins; Mitochondria; Progeria
PubMed: 29112121
DOI: 10.3390/ijms18112350 -
Circulation Jul 2014
Topics: Diphosphonates; Female; Humans; Imidazoles; Lamin Type A; Male; Nuclear Proteins; Piperidines; Pravastatin; Progeria; Protein Precursors; Protein Prenylation; Pyridines; Zoledronic Acid
PubMed: 24795391
DOI: 10.1161/CIRCULATIONAHA.114.010648 -
Aging Feb 2024Progeroid disorders are a heterogenous group of rare and complex hereditary syndromes presenting with pleiotropic phenotypes associated with normal aging. Due to the...
Progeroid disorders are a heterogenous group of rare and complex hereditary syndromes presenting with pleiotropic phenotypes associated with normal aging. Due to the large variation in clinical presentation the diseases pose a diagnostic challenge for clinicians which consequently restricts medical research. To accommodate the challenge, we compiled a list of known progeroid syndromes and calculated the mean prevalence of their associated phenotypes, defining what we term the 'progeria phenome'. The data were used to train a support vector machine that is available at https://www.mitodb.com and able to classify progerias based on phenotypes. Furthermore, this allowed us to investigate the correlation of progeroid syndromes and syndromes with various pathogenesis using hierarchical clustering algorithms and disease networks. We detected that ataxia-telangiectasia like disorder 2, spastic paraplegia 49 and Meier-Gorlin syndrome display strong association to progeroid syndromes, thereby implying that the syndromes are previously unrecognized progerias. In conclusion, our study has provided tools to evaluate the likelihood of a syndrome or patient being progeroid. This is a considerable step forward in our understanding of what constitutes a premature aging disorder and how to diagnose them.
Topics: Humans; Progeria; Aging, Premature; Aging; Phenotype; Growth Disorders; Cockayne Syndrome
PubMed: 38345566
DOI: 10.18632/aging.205537 -
The EMBO Journal Jan 2023Hutchinson-Gilford progeria syndrome (HGPS) is a lethal premature aging disorder without an effective therapeutic regimen. Because of their targetability and influence...
Hutchinson-Gilford progeria syndrome (HGPS) is a lethal premature aging disorder without an effective therapeutic regimen. Because of their targetability and influence on gene expression, microRNAs (miRNAs) are attractive therapeutic tools to treat diseases. Here we identified that hsa-miR-59 (miR-59) was markedly upregulated in HGPS patient cells and in multiple tissues of an HGPS mouse model (Lmna ), which disturbed the interaction between RNAPII and TFIIH, resulting in abnormal expression of cell cycle genes by targeting high-mobility group A family HMGA1 and HMGA2. Functional inhibition of miR-59 alleviated the cellular senescence phenotype of HGPS cells. Treatment with AAV9-mediated anti-miR-59 reduced fibrosis in the quadriceps muscle, heart, and aorta, suppressed epidermal thinning and dermal fat loss, and yielded a 25.5% increase in longevity of Lmna mice. These results identify a new strategy for the treatment of HGPS and provide insight into the etiology of HGPS disease.
Topics: Mice; Animals; Progeria; Antagomirs; Cellular Senescence; MicroRNAs; Phenotype
PubMed: 36382717
DOI: 10.15252/embj.2022110937 -
Nucleus (Austin, Tex.) Dec 2018Progeroid syndromes induced by mutations in lamin A or in its interactors - named progeroid laminopathies - are model systems for the dissection of the molecular... (Review)
Review
Progeroid syndromes induced by mutations in lamin A or in its interactors - named progeroid laminopathies - are model systems for the dissection of the molecular pathways causing physiological and premature aging. A large amount of data, based mainly on the Hutchinson Gilford Progeria syndrome (HGPS), one of the best characterized progeroid laminopathy, has highlighted the role of lamins in multiple DNA activities, including replication, repair, chromatin organization and telomere function. On the other hand, the phenotypes generated by mutations affecting genes directly acting on DNA function, as mutations in the helicases WRN and BLM or in the polymerase polδ, share many of the traits of progeroid laminopathies. These evidences support the hypothesis of a concerted implication of DNA function and lamins in aging. We focus here on these aspects to contribute to the comprehension of the driving forces acting in progeroid syndromes and premature aging.
Topics: Animals; DNA; DNA Replication; Genomic Instability; Humans; Progeria
PubMed: 29936894
DOI: 10.1080/19491034.2018.1476793