Recent findings have shown the presence of systemic oxidative stress in a severe neurodevelopmental disorder (Rett syndrome - RTT), the second most common cause of mental retardation in the female gender. In up to 90% of patients, the clinical features of RTT have been associated with the mutation in the methyl-CpG-binding protein-2 gene (MeCP2). In the present study we have surprisingly found that compared to healthy subjects, RTT patients have higher plasma levels of total cholesterol, HDL and LDL. This result was the consequence of decreased levels of SRB1 (a receptor mainly involved in meditating the uptake of HDL-derived cholesterol and cholesteryl ester). Using immunogold and immunohistochemistry techniques we have shown that fibroblasts, isolated from cutaneous tissue of RTT patients, have a dramatic and significant decrease of SRB1 protein level with respect to the healthy subjects. The lost of SRB1 in RTT fibroblasts was a consequence of the increase ubiquitination (shown by double immunofluorence and immunoprecipitation assay) of the receptor due to its covalent binding with 4-hydroxy-2-nonenal (HNE). In addition, there was also a significant decrease at the mRNA levels between RTT and control, with RTT fibroblasts having circa 80% less mRNA compared to the fibroblasts isolated from the healthy subjects.

The reduced level of SRB1 and therefore the inability to uptake optimum levels of cholesterol could partially explain: 1) the neuronal alterations; 2) the increased plasma cholesterol levels; 3) the low levels of liposoluble tissue antioxidants, and possibly 4) the microcephaly found in the RTT patients.