Mecp2 deficiency causes oxidative brain damage in Rett syndrome murine models.

Rett syndrome (RTT) is a neurodevelopmental disorder caused by loss-of-function mutations in the X-linked gene encoding methyl-CpG binding protein 2 (MECP2). The molecular mechanisms through which MECP2 mutations lead to disruptions of brain function are not fully understood. The presence of high circulating levels of oxidative stress (OS) markers in RTT patients suggests the involvement of OS in the pathogenesis and progression of the disease. However, the nature of the relationship between OS derangement and MeCP2 deficiency remains to be elucidated, while the occurrence and the features of an OS-driven brain damage in RTT remains to be demonstrated. To explore these critical points, several OS markers were assayed in brain and blood from Mecp2-null (pre-symptomatic, symptomatic) and Mecp2-308 mutated (symptomatic hemizygous male, and heterozygous female) mice and compared to those of wild-type littermates. Measured OS markers included non-protein-bound iron (NPBI), isoprostanes (IsoPs) [F2-IsoPs, F2-Dihomo-IsoPs, F4-neuroprostanes (F4-NeuroPs)] and 4-hydroxy-2-nonenal protein adducts (4-HNE PAs). Oxidative brain damage 1) occurs in both Mecp2-null and Mecp2-308 models of RTT; 2) precedes the onset of symptoms; 3) is mirrored in plasma by increased OS markers in both pre-symptomatic and symptomatic phase. This study provides the first experimental evidence on the causal relationship between Mecp2 deficiency and oxidative brain damage in murine models of RTT, thus paving the way towards new potential therapeutic targets, and pre-clinical diagnostic screening.