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

细胞朊病毒蛋白（PrPC）与致病蛋白构象体如PrPSc、Aβ和β-突触核蛋白的相互作用可在不存在感染性朊病毒传播的情况下激活神经毒性途径。这种活性与PrPC作为神经保护信号传导途径的激活剂的生理功能相互关联，因为神经保护和神经毒性信号传导都与PrPC的非结构化N-末端结构域（N-PrP）相关。为了对潜在机制提供新的见解，研究提案将确定N-PrP的新型配体以及致病相互作用者如何滥用PrPC进行毒性信号传导。此外，我们将分析PrPC的蛋白水解加工作为调节和扩大PrP活性的开关的作用，并在体内生理和病理生理条件下研究PrP相互作用组。最后，我们将调查的N-末端结构域的PrPC在四足动物和它的活动，以支持神经毒性和神经保护信号通路的共同进化。实验方法包括体外测定、哺乳动物细胞培养模型（包括原代神经元）和神经退行性疾病的小鼠模型，以解决以下具体目标。

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.