A roadmap for investigating the role of the prion protein in depression associated with neurodegenerative disease.

The physiological properties of the native, endogenous prion protein (PrP(C)) is a matter of concern, due to its pleiotropic functions and links to neurodegenerative disorders and cancer. In line with our hypothesis that the basic function of PrP(C) is to serve as a cell surface scaffold for the assembly of signaling modules, multiple interactions have been identified of PrP(C) with signaling molecules, including neurotransmitter receptors. We recently reported evidence that PrP(C) may modulate monoaminergic neurotransmission, as well as depressive-like behavior in mice. Here, we discuss how those results, together with a number of other studies, including our previous demonstration that both inflammatory and behavioral stress modulate PrP(C) content in neutrophils, suggest a distributed role of PrP(C) in clinical depression and inflammation associated with neurodegenerative diseases. An overarching understanding of the multiple interventions of PrP(C) upon physiological events may both shed light on the pathogenesis of, as well as help the identification of novel therapeutic targets for clinical depression, Prion and Alzheimer's Diseases.