A Comparison of Adult and Childhood Progerias: Werner Syndrome and Hutchinson-Gilford Progeria Syndrome

Wt, Brown; Fj, Kieras; Ge, Houck; Dutkowski, Regina; Ec, Jenkins

doi:10.1007/978-1-4684-7853-2_10

Cited by 41 publications

(17 citation statements)

References 10 publications

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“…To date, most progeroid syndromes for which genes and patho-physiological mechanisms have been identified are monogenic and classified as segmental, insofar as they are associated with many, but not all, of the clinical characteristics seen in normal ageing processes [4,5]. The validity of progeroid syndromes as ageing models is disputed, however, as they are not simply a global acceleration of age-linked pathology [6].…”

Section: Premature Ageing Disorders and Werner Syndromementioning

confidence: 99%

Use of p38 MAPK Inhibitors for the Treatment of Werner Syndrome

et al. 2010

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Werner syndrome provides a convincing model for aspects of the normal ageing phenotype and may provide a suitable model for therapeutic interventions designed to combat the ageing process. Cultured primary fibroblast cells from Werner syndrome patients provide a powerful model system to study the link between replicative senescence in vitro and in vivo pathophysiology. Genome instability, together with an increased pro-oxidant state, and frequent replication fork stalling, all provide plausible triggers for intracellular stress in Werner syndrome cells, and implicates p38 MAPK signaling in their shortened replicative lifespan. A number of different p38 MAPK inhibitor chemotypes have been prepared rapidly and efficiently using microwave heating techniques for biological study in Werner syndrome cells, including SB203580, VX-745, RO3201195, UR-13756 and BIRB 796, and their selectivity and potency evaluated in this cellular context. Werner syndrome fibroblasts treated with a p38 MAPK inhibitor reveal an unexpected reversal of the accelerated ageing phenotype. Thus the study of p38 inhibition and its effect upon Werner pathophysiology is likely to provide new revelations into the biological mechanisms operating in cellular senescence and human ageing in the future.

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Section: Premature Ageing Disorders and Werner Syndromementioning

confidence: 99%

Use of p38 MAPK Inhibitors for the Treatment of Werner Syndrome

et al. 2010

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“…Features occurring in the skin during late adulthood of normal individuals, such as hair greying, hair loss, and skin thinning, occur in the first few years of life in subjects with HGPS [1-3]. Most subjects die in their teenage years from cardiac complications of coronary artery disease or stroke due to widespread arteriosclerosis [2]. …”

Section: Introductionmentioning

confidence: 99%

Dermal fibroblasts in Hutchinson-Gilford progeria syndrome with the lamin A G608G mutation have dysmorphic nuclei and are hypersensitive to heat stress

et al. 2005

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Background: Hutchinson-Gilford progeria syndrome (HGPS, OMIM 176670) is a rare sporadic disorder with an incidence of approximately 1 per 8 million live births. The phenotypic appearance consists of short stature, sculptured nose, alopecia, prominent scalp veins, small face, loss of subcutaneous fat, faint mid-facial cyanosis, and dystrophic nails. HGPS is caused by mutations in LMNA, the gene that encodes nuclear lamins A and C. The most common mutation in subjects with HGPS is a de novo single-base pair substitution, G608G (GGC>GGT), within exon 11 of LMNA. This creates an abnormal splice donor site, leading to expression of a truncated protein.

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“…WS is also associated with an increase in neoplasms of mesenchymal origin (Goto et al, 1996). With the exception of central nervous system degeneration, this disease provides a convincing mimic of the normal ageing phenotype (Brown et al, 1985) and is thus an important model disease.…”

Section: Introductionmentioning

confidence: 99%

Telomere-based proliferative lifespan barriers in Werner-syndrome fibroblasts involve both p53-dependent and p53-independent mechanisms

Davis

Singhrao

Wyllie

et al. 2003

Journal of Cell Science

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Werner-syndrome fibroblasts have a reduced in vitro life span before entering replicative senescence. Although this has been thought to be causal in the accelerated ageing of this disease, controversy remains as to whether Werner syndrome is showing the acceleration of a normal cellular ageing mechanism or the occurrence of a novel Werner-syndrome-specific process. Here, we analyse the signalling pathways responsible for senescence in Werner-syndrome fibroblasts. Cultured Werner-syndrome (AG05229) fibroblasts senesced after ~20 population doublings with most of the cells having a 2N content of DNA. This was associated with hypophosphorylated pRb and high levels of p16Ink4a and p21Waf1. Senescent AG05229 cells re-entered the cell cycle following microinjection of a p53-neutralizing antibody. Similarly, production of the human papilloma virus 16 E6 oncoprotein in presenescent AG05229 cells resulted in senescence being bypassed and extended cellular life span. Werner-syndrome fibroblasts expressing E6 did not proliferate indefinitely but reached a second proliferative lifespan barrier, termed Mint, that could be bypassed by forced production of telomerase in post-M1 E6-producing cells. The conclusions from these studies are that: (1) replicative senescence in Werner-syndrome fibroblasts is a telomere-induced p53-dependent event; and (2) the intermediate lifespan barrier Mint is also a telomere-induced event, although it appears to be independent of p53. Werner-syndrome fibroblasts resemble normal human fibroblasts for both these proliferative lifespan barriers, with the strong similarity between the signalling pathway linking telomeres to cell-cycle arrest in Werner-syndrome and normal fibroblasts providing further support for the defect in Werner syndrome causing the acceleration of a normal ageing mechanism

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A Comparison of Adult and Childhood Progerias: Werner Syndrome and Hutchinson-Gilford Progeria Syndrome

Cited by 41 publications

References 10 publications

Use of p38 MAPK Inhibitors for the Treatment of Werner Syndrome

Use of p38 MAPK Inhibitors for the Treatment of Werner Syndrome

Dermal fibroblasts in Hutchinson-Gilford progeria syndrome with the lamin A G608G mutation have dysmorphic nuclei and are hypersensitive to heat stress

Telomere-based proliferative lifespan barriers in Werner-syndrome fibroblasts involve both p53-dependent and p53-independent mechanisms

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