Assessing the role of stress signalling via p38 MAP kinase in the premature senescence of Ataxia Telangiectasia and Werner syndrome fibroblasts

Abstract

The premature ageing Ataxia Telangiectasia (AT) and Werner syndromes (WS) are associated with accelerated cellular ageing. Young WS fibroblasts have an aged appearance and activated p38 MAP kinase, and treatment with the p38 inhibitor SB230580 extends their lifespan to within the normal range. SB203580 also extends the replicative lifespan of normal adult dermal fibroblasts, however, the effect is much reduced when compared to WS cells, suggesting that WS fibroblasts undergo a form of stress-induced premature senescence (SIPS). A small lifespan extension is seen in AT cells, which is not significant compared to normal fibroblasts, and the majority of young AT cells do not have an aged appearance and lack p38 activation, suggesting that the premature ageing does not result from SIPS. The lack of p38 activation is supported by the clinical manifestation, since AT is not associated with inflammatory disease, whereas WS individuals are predisposed to atherosclerosis, type II diabetes and osteoporosis, conditions known to be associated with p38 activation.

Mitochondrial dysfunction in some oxidative stress-related genetic diseases: Ataxia-Telangiectasia, Down Syndrome, Fanconi Anaemia and Werner Syndrome

“…Thus, the WS-associated genetic defect is related to impaired maintenance of DNA integrity, and has implications for the presence of oxidative stress in the WS phenotype (von Kobbe et al 2004). The roles of oxidative stress in WS have been investigated in studies of WRNp functions (von Kobbe et al 2004;Bukowy et al 2008;Harrigan et al 2007), consistent with in vitro (Davis and Kipling 2009) and animal studies (Deschênes et al 2005;Massip et al 2006;Moore et al 2008). Our previous reports provided evidence for excess oxidative stress in blood cells and body fluids from WS patients versus controls and versus patients with other genetic diseases (Pagano et al 2005b;Lloret et al 2008a).…”

ERS statement on the multidisciplinary respiratory management of ataxia telangiectasia

“…The latter is probably secondary to poor nutrition and early confinement to wheelchair. There is animal experimental evidence that ATM deficiency leads to an osteoporotic phenotype in mice due to reduced bone formation and increased bone resorption [33] or accelerated cellular ageing [34].…”

Use of p38 MAPK Inhibitors for the Treatment of Werner Syndrome

“…Thus, SB203580 essentially prevented the accelerated ageing seen in primary WS cells. SB203580 treatment had no, or minimally, significant effects on normal cells (for effects on growth rate and lifespan see Figure 8b) [88,101]­, so this finding suggested that the abnormal growth, enlarged morphology and premature senescence of WS cultures resulted from the activation of an SB203580-suppressible pathway. …”