Increased susceptibility to dicarbonyl stress in Rett syndrome

Rett syndrome (RTT) is a rare neurodevelopmental disorder, resulting from mutations in the Xlinked methyl-CpG-binding protein 2 (MECP2) gene. Recent studies have shown that oxidative stress (OS) and subclinical inflammatory status play a key role in RTT pathogenesis. Methylglyoxal (MG), an endogenous cytotoxic α-oxoaldehyde, is the main precursor of advanced glycation end products (AGEs), by inducing OS in several pathological conditions. On this basis, a possible involvement of the MG-targeting defense system in the RTT-related OxInflammation processes may be hypothesized. Two enzymes, GLO-1 and GLO-2, along with glutathione (GSH), are the main responsible for MG scavenging, with GLO-2 catalyzing the rate limiting step of this system. In the present study, we have evaluated the levels of GLOs (mRNA, protein, activity), the level of MGdependent protein damage and the cellular response to exogenous MG in fibroblasts from RTT patients and healthy volunteers (N=6 per group). Our results revealed that in Rett syndrome, while there were no significant changes in the levels of GLO-1 transcript, protein or specific activity, the GLO-2 enzymatic activity was significantly increased. Nevertheless, Rett syndrome fibroblasts did not show alterations in the levels of MG- induced damage, but at the same time, they seemed to be more prone to exogenous MG-induced stress. Our findings suggest that patients with RTT possibly show altered dicarbonyl stress defense system that may render cells more susceptible to further glycating insults due to the already challenged GLOs machinery.