Biomarkers of lipid oxidative damage in Rett syndrome

Lipid peroxidation is a critical component of oxidative stress (OS), a biological condition determined by the imbalance between prooxidants and the antioxidant system and involved in inflammation, carcinogenesis, neurodegeneration, and development. In particular, free radicals and specifically radical oxygen species (ROS) are able to attack polyunsaturated fatty acids (PUFAs) of cell membranes thus generating a family of α,β-unsaturated reactive aldehydes, such as 4-hydroxy-2-nonenal (4HNE), and prostaglandin-like end products termed isoprostanes (IsoPs), produced via the nonenzymatic free radical-initiated peroxidation of either arachidonic acid (F2-IsoPs), adrenic acid (F2-dihomo-IsoPs), or docosahexaenoic acid (F4-IsoPs or F4-neuroprostanes). Here, we explored the value of IsoPs as biomarkers in Rett syndrome (RTT), a relatively rare form of autism affecting almost exclusively females, caused in the overwhelming majority of cases by mutation in the X-linked methyl-CpG-binding protein 2 gene (MeCP2) and for which no definitive cure exists. Our investigations, focused on plasma IsoP changes as a function of natural history, clinical severity, and type of mutation in a large RTT patients cohort, indicate the relevance of plasma IsoPs as biomarkers of the disease and strongly suggest the importance of lipid peroxidation in the pathogenesis of this autism spectrum disorder, with profound implications for new potential treatment strategies.