MITOCHONDRIAL ABNORMALITIES AND OXINFLAMMATORY MECHANISMS IN THE PRESYMPTOMATIC-TO-SYMPTOMATIC TRANSITION OF RETT SYNDROME

Rett syndrome (RTT) is a neurodevelopmental disorder primarily affecting girls, characterized by an initial period of normal development followed by progressive cognitive and motor decline. Mutations in the MECP2 gene, a key regulator of gene expression, are the main genetic cause of RTT, while mechanisms driving onset and progression remain incompletely understood. Mitochondrial dysfunction, oxidative stress, and inflammation are increasingly implicated in RTT pathogenesis.
In this study, we characterized molecular events underlying the transition from presymptomatic to symptomatic stages by integrating in vitro and ex vivo approaches.
Primary cortical neurons from MeCP2 knockout mice were analyzed at DIV6, DIV12, and DIV18. Mitochondrial morphology and membrane potential were assessed via high-content imaging, while Western blot and RT-qPCR evaluated proteins and genes regulating mitochondrial dynamics, biogenesis, and inflammation. Complementary ex vivo analyses were performed on brain tissues from MeCP2 knockout mice at postnatal day 0 ((P0, presymptomatic) and postnatal day 49 (P49, symptomatic).
Our preliminary data reveal marked mitochondrial impairments in MeCP2-null neurons at all stages, with altered expression of genes and proteins controlling mitochondrial homeostasis. Ex vivo tissues show stage-dependent and partially distinct mitochondrial phenotypes not fully reproduced in vitro, indicating additional in vivo complexity. These alterations associate with increased reactive oxygen species, promoting oxidative stress and inflammatory activation. Overall, mitochondrial dysfunction is an early, persistent hallmark of RTT and a key contributor to progression. These findings highlight potential targets for future therapeutic strategies. This work was supported by project Prot. 2022FSPCH2 (PRIN PNRR, Next Generation EU, CUP mJ53D23012750001).