POTENTIAL NEUROPROTECTIVE EFFECTS OF EPOXY FATTY ACIDS IN RETT SYNDROME

Rett syndrome (RTT) is a neurodevelopmental disorder affecting 1:10000 young females worldwide, mainly caused by mutations in the X-linked MECP2 gene. One of the main clinical features in RTT is altered cholesterol metabolism, which can lead to neuroinflammation, oxidative stress and defective synaptogenesis. The current study aims to investigate how altered cholesterol metabolism could potentially contribute to the pathophysiology of RTT. Abnormal accumulation of unesterified cholesterol was observed in primary RTT fibroblasts carrying different mutations compared with healthy donor (HD) fibroblasts. Similarly, altered cholesterol levels were also detected in primary hippocampal neuronal cultures derived from heterozygous female Mecp2^+/− mice. In this context, the therapeutic benefits of Epoxy Fatty Acids (EpFAs) were investigated to study their ability to restore cholesterol homeostasis by regulating the activity of the 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), the rate-limiting enzyme of cholesterol synthesis. Treatments with epoxy oleic, epoxy linoleic and epoxy linolenic acids reduced free cholesterol accumulation and restored metabolic function in RTT fibroblasts. Lovastatin, an HMGCR inhibitor previously tested in RTT murine models, was also included as a reference compound and similarly reduced free cholesterol levels in RTT fibroblasts. The ultimate goal of the project is to validate the role of EpFAs in modulating HMGCR expression. Notably, increased levels of linoleic acid epoxides (9,10- and 12,13-epoxyoctadecenoic acid, EpOME) were found to modulate AMPK phosphorylation levels, thereby inhibiting HMGCR activity. Overall, this study highlights the therapeutic potential of EpFAs in treating metabolic abnormalities associated with cholesterol dysregulation in RTT, supporting them as promising candidates for future therapeutic strategies.