A novel insertional mutation in the prion protein gene: clinical and bio-molecular findings.

A young man, presenting with early onset of personality and behavioural changes followed by slowly progressive cognitive impairment associated with marked bi-parietal cerebral atrophy, was found to carry a novel seven extra-repeat insertional mutation in the prion protein gene (PRNP). In vitro, the mutated recombinant prion protein (PrP) showed biochemical properties that were consistent with pathological PrP variants. Our results further underline the heterogeneity of neurological pictures associated with insertional mutations of PRNP, indicating the diagnostic difficulties of sporadic cases with early-onset atypical dementia.

NF-κB-dependent cytokine secretion controls Fas expression on chemotherapy-induced premature senescent tumor cells.

Induction of a senescent phenotype in tumor cells has been linked to anticancer immune response, however, the molecular mechanisms mediating these phenomenon have not yet been determined. In this study, we present evidence that induction of premature senescence in human cancer cell lines induces Fas expression, and loss of resistance to Fas-induced apoptosis. Triggering of Fas by using the agonistic antibody CH11 or the recombinant ligand APO010, activates an apoptotic pathway responsible for cell death. Secretion of pro-inflammatory cytokines by the senescent cells, particularly TNF-α and IFN-γ, mediates Fas upregulation. Indeed, treatment of proliferating cancer cell lines with TNF-α and IFN-γ, upregulates Fas expression, while blocking TNF-α and IFN-γ by using neutralizing antibodies, decreases Fas expression in senescent cells. We also demonstrate that NF-κB has a central role in controlling the senescence-associated secretory phenotype (SASP) by the premature senescent cells, and that TNF-α and IFN-γ, transcriptionally controlled by NF-κB, are the main mediators of Fas upregulation. Our data suggest the existence of an NF-κB-dependent autocrine loop, mediated by TNF-α and IFN-γ, responsible for expression of Fas on the surface of senescent cells, and for their killing.