Regulation of cell fate and function by sterol homeostasis

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PROJECT SUMMARY Loss of cholesterol homeostasis has been associated with a host of neurodevelopmental and neurodegenerative disorders, though the precise mechanisms underlying cholesterol-mediated effects are unclear. While inherited mutations within cholesterol synthetic enzymes are known to induce neurodevelopmental deficits, the mechanisms behind cellular phenotypes resulting from these biochemical deficits remain largely undefined at the cellular and functional level. Therefore, studies delineating the role of cholesterol metabolism in neurodevelopment and function could have a significant impact on our understanding of potential common mechanisms of disease pathogenesis. Stem cell models exhibiting biochemical defects in the cholesterol synthetic pathway represent a novel biological model to study interactions between abnormal sterol levels and signaling events leading to cellular and functional deficits. Using induced pluripotent stem cell (iPSC) models exhibiting DHCR7 and SC5D mutations, we recently uncovered a unique regulatory role for sterol biosynthesis in the functional interactions between proteins mediating Wnt/β-catenin signaling. Within this proposal, we will test the hypothesis that defects in cholesterol synthesis inhibit normal neurodevelopment at the stem cell level through inhibition of protein-protein interactions, shifting differentiation patterns toward neuronal cell types at the expense of glial cells while inhibiting synaptic function. Aim 1 of this project will utilize genomic sequencing and functional studies in human iPSC derivatives and rodent models to define how defects in cholesterol homeostasis regulate neural specification and function. Aim 2 will correlate the cellular effects of altered cholesterol homeostasis with disrupted protein-protein interactions through biochemical analyses of protein-lipid interactions., In vivo cellular models will also define the kinetics, specificity, and downstream signaling events resulting from cholesterol defects. These experiments will significantly advance our understanding of the role of cholesterol and associated signaling in regulating neurodevelopment and neuronal function, while potentially elucidating the mechanistic underpinnings of cholesterol homeostatic changes in common neurological diseases.