DNA damage accumulation and response in Down syndrome cell model systems

DNA damage may significantly contribute to the etiology of several human diseases, including tumors and neurological disorders. In particular, DNA damage has been associated with many of the latter pathologies, such as Alzheimer disease (AD), and Parkinson disease (PD), but also with Down syndrome (DS). Increased accumulation of DNA lesions, and in particular those produced by oxidative damage, possiblly in association with defects in DNA repair, have been indicated as one of the factors leading to cell death. However, direct mechanisms explaining the origin of such defects are still not fully identified. The aim of this work is to assess the presence of DNA damage and response pathways in DS cells, and in particular, to define whether signaling pathways and DNA repair processes, may be altered in DS cells. To this end, the DNA damage response is being investigated in human fetal and adult skin fibroblasts from euploid and DS donors, as well as murine fibroblasts obtained from Ts65Dn mice, which are a model of DS. The studies are performed in terms of different end-points, i.e. p53 expression, detection of DNA damage through the phosphorylation of histone H2AX, in order to evaluate the presence of endogenous DNA damage and its eventual accumulation during age. Concomitantly, cloning efficiency after oxidative DNA damage, has ben performed The results show that both in human fibroblasts, and in Ts65Dn murine fibroblasts, there is an increase in p53 protein levels already in basal conditions, together with a further increase after DNA damage, as compared with their respective counterpart of fibroblasts from healthy donors. In addition, an increased sensitivity to oxidative DNA damage has been found in human DS fibroblasts, in comparison with normal cells. These results suggest that basal levels of endogenous DNA damage are already present in DS cells, as compared with those from euploid samples, and that DS cells are probably less efficient in dealing with oxidative lesions, possibly due to defects in the BER process. Further investigations are in progress to confirm these findings in line with recent suggestions indicating the oxidative DNA damage as one of the main factors responsible for neuronal death in DS individuals.