The Prion Protein is Embedded in a Molecular Environment that Modulates Transforming Growth Factor β and Integrin Signaling

The prion protein (PrP) is known for its fundamental role in a group of neurodegenerative disorders, aptly called prion diseases. The function of the normal cellular prion protein (PrPC) as well as the underlying molecular mechanisms that lead to neurotoxicity in disease are still unresolved. The previously discovered evolutionary relationship between PrP and ZIP zinc transporters implicated PrPC in morphogenetic reprogramming events but also uncovered surprising differences when comparing signaling pathways downstream of PrPC in separate cellular paradigms. To extend this line of research, we combined CRISPR-Cas9-based genetic engineering to generate four relevant murine PrP-deficient cell models, with quantitative mass spectrometry-based analyses to compare the molecular environment of PrP in these models. Interestingly, a unified theme emerged from these studies that placed PrPC in a specialized membrane domain that modulates TGF beta and integrin signaling.M.Sc