Abstract
Progeroid syndromes show features of accelerated ageing and are used as models for human ageing, of which Werner syndrome (WS) is one of the most widely studied. WS fibroblasts show accelerated senescence that may result from p38 MAP kinase activation since it is prevented by the p38 inhibitor SB203580. Thus, small molecule inhibition of p38-signalling may be a therapeutic strategy for WS. To develop this approach issues such as the in vivo toxicity and kinase selectivity of existing p38 inhibitors need to be addressed, so as to strengthen the evidence that p38 itself plays a critical role in mediating the effect of SB203580, and to find an inhibitor suitable for in vivo use. In this work we used a panel of different p38 inhibitors selected for: (1) having been used successfully in vivo in either animal models or human clinical trials; (2) different modes of binding to p38; and (3) different off-target kinase specificity profiles, in order to critically address the role of p38 in the premature senescence seen in WS cells. Our findings confirmed the involvement of p38 in accelerated cell senescence and identified p38 inhibitors suitable for in vivo use in WS, with BIRB 796 the most effective.
Highlights
Werner Syndrome (WS) is a rare, autosomal recessive human disorder resulting from mutations in the WRN gene, which encodes the RECQ3 DNA helicase [1]
We find that BIRB 796 is 100% effective at inhibiting p38 in the 2 h anisomycin test assay at 10 nM and above (Figure S1b)
Four p38 inhibitors (SB203580, BIRB 796, VX-745 and UR13756) have been used to test the role of p38α MAPK in the premature senescence seen in primary fibroblasts from the premature ageing Werner syndrome
Summary
Werner Syndrome (WS) is a rare, autosomal recessive human disorder resulting from mutations in the WRN gene, which encodes the RECQ3 DNA helicase [1]. E.g., the absence of central nervous system degeneration, WS provides a stunning mimicry of normal ageing and is widely used as a model disease to investigate the mechanisms underlying normal human ageing [2,3]. A key aspect of WS is that WS fibroblasts in vitro have a much reduced replicative capacity compared to normal fibroblasts [4]. This premature senescence has been postulated as a major contributor to the accelerated ageing of mitotic tissues in vivo in this syndrome [2]. WS provides an important model system to investigate the link between replicative senescence in vitro and normal ageing in vivo
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