Rett syndrome (RTT) is a rare neurodevelopmental disorder mainly caused by mutation in the methyl-CpG binding protein 2 gene (MECP2). However, to date, the molecular and pathogenic mechanisms by which MECP2 deficiency drives pathology in RTT remains not fully understood. In the last few years, Oxidative Stress and subclinical inflammation have been both proposed as possible mechanisms for cognitive impairment although the cross-talk among these 2 pathways have not been yet investigated. To address this issue, freshly isolated skin fibroblasts from RTT patients and healthy subjects were challenged with lipopolysaccharides (LPS) and the modulation of NFkB (Nuclear Factor Kappa B) and NRF2 (NF-E2 p45-related factor 2), the main transcription factors involved in inflammatory and antioxidant response, respectively were studied. Our results show a slightly increase in inflammatory and antioxidant response in control cells upon LPS treatment (100ug/ml for 30 minutes), while in RTT cells, this effect was much more evident with a clear p65-NFkB translocation and IL6 and IL8 over-expression. Antioxidant response in RTT cells shows unaltered NRF2 nuclear/cytosol distribution, balanced by its higher DNA binding capacity on ARE-sequences. This possible compensatory mechanism results inefficient in stimulate phase II antioxidant enzymes like NQO1. All together, our findings suggest a possible inhibition of the Nrf2 pathway by p65-NFkB in RTT. Subclinical inflammation, which characterize RTT patients, might explain loss of oxidative balance, thus targeting p65-NFkB may drive more efficient NRF2 transcription.

Antioxidant and Inflammatory Cross-talk in Rett Syndrome

Romani A.
;
PECORELLI, Alessandra;CRIVELLARI, Ilaria;Cervellati C.;Valacchi G.
2018

Abstract

Rett syndrome (RTT) is a rare neurodevelopmental disorder mainly caused by mutation in the methyl-CpG binding protein 2 gene (MECP2). However, to date, the molecular and pathogenic mechanisms by which MECP2 deficiency drives pathology in RTT remains not fully understood. In the last few years, Oxidative Stress and subclinical inflammation have been both proposed as possible mechanisms for cognitive impairment although the cross-talk among these 2 pathways have not been yet investigated. To address this issue, freshly isolated skin fibroblasts from RTT patients and healthy subjects were challenged with lipopolysaccharides (LPS) and the modulation of NFkB (Nuclear Factor Kappa B) and NRF2 (NF-E2 p45-related factor 2), the main transcription factors involved in inflammatory and antioxidant response, respectively were studied. Our results show a slightly increase in inflammatory and antioxidant response in control cells upon LPS treatment (100ug/ml for 30 minutes), while in RTT cells, this effect was much more evident with a clear p65-NFkB translocation and IL6 and IL8 over-expression. Antioxidant response in RTT cells shows unaltered NRF2 nuclear/cytosol distribution, balanced by its higher DNA binding capacity on ARE-sequences. This possible compensatory mechanism results inefficient in stimulate phase II antioxidant enzymes like NQO1. All together, our findings suggest a possible inhibition of the Nrf2 pathway by p65-NFkB in RTT. Subclinical inflammation, which characterize RTT patients, might explain loss of oxidative balance, thus targeting p65-NFkB may drive more efficient NRF2 transcription.
2018
Rett syndrome, oxidative stress, inflammation
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11392/2394384
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