P-368 - Ex-vivo study on Rett syndrome fibroblasts shows altered methylglyoxal-enzymatic scavenging system: a possible new player in Rett pathogenesis

Abstract

Rett syndrome (RTT) is a human neurodevelopmental disorder in which oxidative stress (OS) and sub-clinical inflammation have been shown to be involved in its pathogenesis. Methylglyoxal (MG), an endogenous cytotoxic dicarbonyl compound, is a major precursor of advanced glycation end products (AGEs), which induce OS in several pathophysiogical conditions. On this basis, a possible involvement of the MG-targeting defence system in the RTT-related OxInflammation processes may be hypothesized. Two main enzymes, GLO-1 and -2, along with glutathione (GSH), are crucial in MG detoxification, with GLO-2 catalyzing both the rate limiting step of this pathway, and the restoration of GSH reservoir. In the present work, we have analyzed the levels of GLOs (activity, protein and mRNA) in fibroblasts from RTT subjects and healthy volunteers (N=6 per group). Our results showed that in Rett syndrome, while not significant changes have been noticed for GLO-1 mRNA, activity and protein levels, GLO-2, was significantly increased in terms of enzymatic activity. This led to assume that Rett syndrome patients have a possibly altered di-carbonyls stress defence system that may render cells more susceptible to further glycating insults due to the already challenged GLOs machinery.