Elucidating the physiological function of cellular PrPC using human iPS cel

PrPC is a conserved lipid-raft associated, GPI-anchored cell membrane glycoprotein. Misfolding of cellular PrPC into the pathogenic PrPSc results in Prion disease, an untreatable and fatal neurodegenerative disorder. Prion induced neurotoxicity is preceded by impairment in metabolism of cholesterol and other lipids which are major component of lipid-rafts in affected neurons. Lipid-rafts deregulation has been implicated in diseases like Prion and AD, the mechanism remains unclear. Understanding the function of cellular PrPC may shed light on such pathological mechanisms. Towards this goal, we utilize a human induced pluripotent stem (iPS) cell model system. We generated isogenic PrP knockout (KO) human primary fibroblasts in order to reprogram them into PrP-KO-iPS cells and human neurons. Metabolomics and RNAseq analysis of these PrP-KO human cells show dysregulation in key CNS pathways like glycerophospholipid and cholesterol metabolism. Here we present a systems biological approach combining RNAseq and metabolomics to understand the functional molecular network of PrPC. The knowledge of key pathways in which PrPC  has important implications could aid in the targeted therapy for prion disorders