Mitochondrial and Cellular Homeostasis in Neurodegeneration: Investigating the Effect of Glucosylated Sterols in Cellular and Zebrafish Models

Glycosylated sterols (GlcSt) are lipid molecules characterized by the covalent conjugation of a sterol backbone and a glucose moiety. They are widely distributed in plants, fungi and algae, more rarely found in bacteria and animals, and represent important membrane components. Functionally, they can influence membrane characteristics, cellular responses to stress and affect cellular homeostasis. Alterations in GlcSt levels have indeed been associated with different neurodegenerative disorders. The glycosylated sterol this project will focus on is β-glucosyl sitosterol (BSSG), which has been directly associated with amyotrophic lateral sclerosis-parkinsonism dementia complex (ALS-PDC), a progressive neurodegenerative disease found in specific isolated regions of the Western Pacific. This compound is derived from plants, in particular from cycad seeds, which have historically been linked to disease occurrence in affected populations. Previous experimental studies have shown that BSSG induces dose-dependent neuronal death. In this context, my thesis project aims to investigate the role of GlcSt, in particular BSSG, in neurodegeneration, using in vitro cellular models and in vivo zebrafish models and focusing on their potential contribution to oxidative stress, mitochondrial dysfunction, disruption of iron and hemoglobin metabolism and alterations in cellular pathways associated with neuronal damage.