The intrinsically disordered N-terminal domain of the mammalian prion protein as an integrator of neuroprotective and neurotoxic signaling

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The interaction of the cellular prion protein (PrPC) with pathogenic protein conformers, such as PrPSc, Aβ and -synuclein can activate neurotoxic pathways in the absence of infectious prion propagation. This activity is interconnected with a physiological function of PrPC as an activator of neuroprotective signaling pathways since both neuroprotective and neurotoxic signaling are linked to the unstructured N-terminal domain of PrPC (N-PrP). To provide new insights into underlying mechanisms the research proposal will identify novel ligands of N-PrP and how pathogenic interactors misuse PrPC for toxic signaling. In addition, we will analyze the role of proteolytic processing of PrPC as a switch in regulation and expanding PrP activity and study the PrP interactome under physiological and pathophysiological conditions in vivo. Finally, we will investigate the coevolution of the N-terminal domain of PrPC in tetrapods and its activity to support neurotoxic and neuroprotective signaling pathways. The experimental approaches include in vitro assays, mammalian cell culture models, including primary neurons, and mouse models of neurodegenerative diseases to address the following specific aims.