Full Title: Nrf2-pathway alteration in RTT syndrome
Journal: Free Radical Biology and Medicine
Year of Publication: 2017
Publication Author(s): Ilaria Crivellari, Arianna Romani, Alessandra Pecorelli, Carlo Cervellati, Franco Cervellati, Mascia Benedusi, Joussef Hayek, Giuseppe Valacchi
Rett syndrome (RTT) is a rare neurodevelopmental disorder that affects almost exclusively females; 90% of the classic form is caused by mutations in the X-linked MeCP2 gene and patients exhibits neurological but also multisystemic symptoms after 6–18 months. Oxidative stress (OS) seems to play a role in the pathogenic mechanisms of RTT but the link is still unclear. Several enzymes involved in the antioxidant defense are regulated by Nrf2 (Nuclear erythroid related factor 2), an essential transcription factor activated in response to OS. The aim of our study was to evaluate the activation of Nrf2 pathway in fibroblasts isolated from RTT patients after challenging the cells with 4-HNE, aldehyde which levels have been found significantly high in RTT patients plasma. We found that 5 µM of 4-HNE was able to increase the nuclear translocation of Nrf2 in RTT fibroblasts as demonstrated by DNA binding assay and nuclear Western blot assay. Surprisingly, while 4-HNE treatment increased the gene expression of antioxidant enzymes such as GPX (glutathione peroxidase) and GR (glutathione reductase), their activities were significant corrupted in RTT cells suggesting a possible post-translational modification leading to the inability of RTT patients to fully counteract an oxidative stress challenge and bringing new insights on the possible link between this pathology and an OS state.
Link to Article: https://www.sciencedirect.com/science/article/pii/S0891584917304227