Molecular insights into the premature aging disease progeria

Nuclear integrity and mechanical stability of the nuclear envelope (NE) are conferred by the nuclear lamina, a meshwork of intermediate filaments composed of A- and B-type lamins, supporting the inner nuclear membrane and playing a pivotal role in chromatin organization and epigenetic regulation. During cell senescence, nuclear alterations also involving NE architecture are widely described. In the present study, we utilized induced pluripotent stem cells (iPSCs) upon prolonged in vitro culture as a model to study aging and investigated the organization and expression pattern of NE major constituents. Confocal and four-dimensional imaging combined with molecular analyses, showed that aged iPSCs are characterized by nuclear dysmorphisms, nucleoskeletal components (lamin A/C-prelamin isoforms, lamin B1, emerin, and nesprin-2) imbalance, leading to impaired nucleo-cytoplasmic MKL1 shuttling, actin polymerization defects, mitochondrial dysfunctions, SIRT7 downregulation and NF-kBp65 hyperactivation. The observed age-related NE features of iPSCs closely resemble those reported for premature aging syndromes (e.g., Hutchinson-Gilford progeria syndrome) and for somatic cell senescence. These findings validate the use of aged iPSCs as a suitable cellular model to study senescence and for investigating therapeutic strategies aimed to treat premature aging.

show abstract

“…Importantly, progerin expression has been documented to decrease the expression levels of lamin B1 [13]. …”

Section: Discussionmentioning

confidence: 99%

Aged induced pluripotent stem cell (iPSCs) as a new cellular model for studying premature aging

Petrini

Borghi

D’Oria

et al. 2017

Aging

View full text Add to dashboard Cite

show abstract

“…In a mouse model carrying a progeric mutation within the Lmna gene, inhibition of the Wnt pathway was reported, leading to reduced function of the transcription factor LEF1, which regulates expression of ECM proteins (Hernandez, Roux et al 2010). These studies suggest that deficiencies in Wnt signalling could cause changes in ECM composition, contributing to vascular stiffness in HGPS (Vidak and Foisner 2016). …”

Section: Molecular Mechanisms Behind Cellular Decline In Hgpsmentioning

confidence: 99%

“…Lamin-associated diseases or laminopathies encompass a range of phenotypes with different tissue pathologies, including muscular dystrophy disorders (e.g., Emery-Dreyfus Muscular Dystrophy or EDMD), peripheral neuropathies (e.g. Charcot-Marie-Tooth-Disease type 2B1 or CMT2B), lipodystrophies, as well as premature aging syndromes such as Hutchinson Gilford Progeria Syndrome (HGPS), Atypical Werner Syndrome (AWS), and restrictive dermopathy (RD) (Worman, Fong et al 2009, Gordon, Rothman et al 2014, Gonzalo and Kreienkamp 2015, Vidak and Foisner 2016). Despite intensive research, the relationships between genotypes and phenotypes in laminopathies remain poorly understood (Smith, Kudlow et al 2005, Bertrand, Chikhaoui et al 2011).…”

Section: Introductionmentioning

confidence: 99%

Hutchinson-Gilford Progeria Syndrome: A premature aging disease caused by LMNA gene mutations

Gonzalo

Kreienkamp

Askjaer

2017

Ageing Research Reviews

217

210

View full text Add to dashboard Cite

Products of the LMNA gene, primarily lamin A and C, are key components of the nuclear lamina, a proteinaceous meshwork that underlies the inner nuclear membrane and is essential for proper nuclear architecture. Alterations in lamin A and C that disrupt the integrity of the nuclear lamina affect a whole repertoire of nuclear functions, causing cellular decline. In humans, hundreds of mutations in the LMNA gene have been identified and correlated with over a dozen degenerative disorders, referred to as laminopathies. These diseases include neuropathies, muscular dystrophies, lipodystrophies, and premature aging diseases. This review focuses on one of the most severe laminopathies, Hutchinson-Gilford Progeria Syndrome (HGPS), which is caused by aberrant splicing of the LMNA gene and expression of a mutant product called progerin. Here, we discuss current views about the molecular mechanisms that contribute to the pathophysiology of this devastating disease, as well as the strategies being tested in vitro and in vivo to counteract progerin toxicity. In particular, progerin accumulation elicits nuclear morphological abnormalities, misregulated gene expression, defects in DNA repair, telomere shortening, and genomic instability, all of which limit cellular proliferative capacity. In patients harboring this mutation, a severe premature aging disease develops during childhood. Interestingly, progerin is also produced in senescent cells and cells from old individuals, suggesting that progerin accumulation might be a factor in physiological aging. Deciphering the molecular mechanisms whereby progerin expression leads to HGPS is an emergent area of research, which could bring us closer to understanding the pathology of aging.

show abstract

“…One in particular bears mentioning here, Hutchinson–Gilford progeria syndrome. This results from defects in lamin A, with consequences for the structural stability of the nucleus, and its gene expression (Vidak and Foisner 2016). Nuclei frequently have a thickened lamina (Worman and Courvalin 2005), and are less resistant to mechanical stress (Zhang et al 2011).…”

Section: Nuclear Shape and Structure In Pathologymentioning

confidence: 99%

Nuclear morphologies: their diversity and functional relevance

2016

View full text Add to dashboard Cite

Studies of chromosome and genome biology often focus on condensed chromatin in the form of chromosomes and neglect the non-dividing cells. Even when interphase nuclei are considered, they are often then treated as interchangeable round objects. However, different cell types can have very different nuclear shapes, and these shapes have impacts on cellular function; indeed, many pathologies are linked with alterations to nuclear shape. In this review, we describe some of the nuclear morphologies beyond the spherical and ovoid. Many of the leukocytes of the immune system have lobed nuclei, which aid their flexibility and migration; smooth muscle cells have a spindle shaped nucleus, which must deform during muscle contractions; spermatozoa have highly condensed nuclei which adopt varied shapes, potentially associated with swimming efficiency. Nuclei are not passive passengers within the cell. There are clear effects of nuclear shape on the transcriptional activity of the cell. Recent work has shown that regulation of gene expression can be influenced by nuclear morphology, and that cells can drastically remodel their chromatin during differentiation. The link between the nucleoskeleton and the cytoskeleton at the nuclear envelope provides a mechanism for transmission of mechanical forces into the nucleus, directly affecting chromatin compaction and organisation.

show abstract

Molecular insights into the premature aging disease progeria

Cited by 96 publications

References 182 publications

Aged induced pluripotent stem cell (iPSCs) as a new cellular model for studying premature aging

Aged induced pluripotent stem cell (iPSCs) as a new cellular model for studying premature aging

Hutchinson-Gilford Progeria Syndrome: A premature aging disease caused by LMNA gene mutations

Nuclear morphologies: their diversity and functional relevance

Contact Info

Product

Resources

About