Mechanisms underlying neural phenotypes of cholesterol synthesis disorders

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. Studies delineating the role of cholesterol metabolism in nervous system development and function could have a significant impact on our understanding of potential common mechanisms of disease pathogenesis. While changes in cholesterol and lipid signaling have previously been associated with conditions such as Parkinson’s disease and Huntington’s disease, disorders arising from errors in cholesterol synthesis mechanisms are unequivocally linked to changes in cholesterol homeostasis, producing severely debilitating and potentially lethal phenotypes in patient populations. Smith-Lemli-Opitz syndrome (SLOS), caused by mutations in the enzyme DHCR7 catalyzing the final step in cholesterol synthesis, is the prototypical and best studied cholesterol synthesis disorder. Patients exhibit severe cognitive impairment, decreased motor skills, and autistic behaviors. However, no therapeutic options exist to target neurological symptoms. Using induced pluripotent stem cells (iPSCs), we have uncovered novel neural phenotypes associated with changes in cholesterol synthesis and have identified a unique role for Wnt signaling in generating these phenotypes. Within this project, we will further define the effects of cholesterol synthesis mechanisms on neurodevelopment and function, while also delineating a specific role for Wnt signaling proteins in leading to neural pathologies. Aim 1 of this project will utilize genomic sequencing and functional assays in iPSC derivatives to define how defects in cholesterol homeostasis regulate neural specification and function. Aim 2 will correlate the effects of altered cholesterol homeostasis with disrupted Wnt signaling during functional neurodevelopment and examine the in vivo effects of Wnt modulation on neuronal function. Aim 3 will determine the mechanistic relationship between Wnt signaling proteins and cholesterol defects through analysis of lipid-protein and protein-protein interactions in varying environmental conditions. These experiments will significantly advance our understanding of the role of cholesterol and associated signaling in regulating neurodevelopment and neuronal function. These findings may lead to the identification of novel therapeutic targets for patients suffering from cholesterol synthesis disorders, while elucidating the mechanistic underpinnings of cholesterol homeostatic changes in common neurological diseases.