On the role of copper and the Prion protein in cellular aging In 1961, Prof. L. Hayflick lays the foundations of cellular aging with theory of replicative senescence. It was subsequently shown that stress can trigger a premature senescence, called Stress-induced premature senescence (SIPS). Since then, the list of actors involved in senescence is growing with a little consideration for metals. Copper plays an important role in the living world as it is the catalyst for many biochemical reactions and may be involved in the structure and function of proteins. The importance of copper homeostasis during aging has been demonstrated in a filamentous fungus Podospora anserina. The results of this study provide new evidence suggesting that the link between copper homeostasis and aging can not be restricted to P. anserina, but is conserved. The first part of this work showed that copper is involved in senescence of WI-38 human diploid fibroblasts(HDFs). Using different techniques, we showed for the first time at the cellular level, an accumulation of copper in FDHs during replicative senescence. We also showed that copper could play an active role in establishing the senescent phenotype. Indeed, incubation with an copper-enriched medium generates an oxidative stress,an antioxidant response but also the premature appearance of senescence markers. The latter phenomenon is dependent of the oxidative stress generated by copper and p38MAPK. Another part of this work concerns the role of Prion protein (PrP) in senescence. We have shown that PrP is overexpressed in PBMC from elderly compared with young people, in HDFs in replicative senescence and in premature senescence induced by copper and other oxidative stresses. WI-38 HDFs incubated with copper-enriched medium showed an overexpression of PrP under its normal conformational form (PrPc) which is localized in both cytoplasm and nucleus. We showed that the invalidation of PrP expression by specific siRNAs already induces the appearance of premature senescence. This invalidation seems to increase ROS production and DNA damages. These results suggest that PrP plays a protective role against oxidative stress, DNA damages and senescence. This work highlights the fact that metals such as copper can play a role in the mechanisms of senescence.
Rôle du cuivre et de la protéine Prion dans le vieillissement cellulaire
Boilan, E. (Author). 19 Oct 2012
Student thesis: Doc types › Doctor of Sciences