Modulation of oxidative stress response in neurodevelopment disorders. The case of the Rett syndrome variants: MECP2 and CDKL5

Full Title: Modulation of oxidative stress response in neurodevelopment disorders. The case of the Rett syndrome variants: MECP2 and CDKL5

Journal: Free Radical Biology and Medicine

Year of Publication: 2017

PHHI Author(s): Giuseppe Valacchi
Publication Author(s): Alessandra Pecorelli, Carlo Cervellati, Joussef Hayek, Giuseppe Valacchi

Abstract:

Rett syndrome (RTT) variants are rare neurodevelopmental disorders caused by mutations in the X-linked MECP2 or CDKL5 genes. Because CDKL5 mediates MeCP2 phosphorylation and CDKL5 is a MeCP2-repressed target gene, it is possible that these proteins share similar molecular pathways. Altered redox status and subclinical inflammation seem to be common denominators between the two RTT variants: increased systemic levels of 4-HNE protein adducts and dysregulated cytokine profiles were reported. The altered redox homeostasis appears to be a critical player in the posttranslational modifications of SRB1, a specific high-density lipoproteins receptor, leading to altered serum lipid profiles in both variants. Although these parallels, Nrf2 system shows an impaired function in both disorders, but with some divergent aspects. CDKL5 show an inability to induce a proper defensive response with a significantly low nuclear Nrf2 translocation after oxidative challenge, while in MECP2 a sustained Nrf2 activation observed in basaline and upon oxidative stress stimulus. These findings reveal common defective pathways related to redox homeostasis between MECP2 and CDKL5. At present, the molecular basis of the discrepancy in the Nrf2 is unknown and requires further investigation in the light of the possibility to develop new therapeutic strategies for these devastating disorders without a cure.

Link to Article: https://www.sciencedirect.com/science/article/pii/S0891584917303635