PrP C as a Transducer of Physiological and Pathological Signals

Abstract

After the discovery of prion phenomenon, the physiological role of the cellular prion protein (PrP ^C ) remained elusive. In the past decades, molecular and cellular analysis has shed some light regarding interactions and functions of PrP ^C in health and disease. PrP ^C , which is located mainly at the plasma membrane of neuronal cells attached by a glycosylphosphatidylinositol (GPI) anchor, can act as a receptor or transducer from external signaling. Although the precise role of PrP ^C remains elusive, a variety of functions have been proposed for this protein, namely, neuronal excitability and viability. Although many issues must be solved to clearly define the role of PrP ^C , its connection to the central nervous system (CNS) and to several misfolding-associated diseases makes PrP ^C an interesting pharmacological target. In a physiological context, several reports have proposed that PrP ^C modulates synaptic transmission, interacting with various proteins, namely, ion pumps, channels, and metabotropic receptors. PrP ^C has also been implicated in the pathophysiological cell signaling induced by β-amyloid peptide that leads to synaptic dysfunction in the context of Alzheimer's disease (AD), as a mediator of Aβ-induced cell toxicity. Additionally, it has been implicated in other proteinopathies as well. In this review, we aimed to analyze the role of PrP ^C as a transducer of physiological and pathological signaling.

Keywords: Alzheimer’s disease; Aβ; PrP; PrPC in CNS; PrPC role; PrPC signaling.

FIGURE 1

PrP structure. PrP^C consists of 253 amino acids, which include the signal peptide (1–22), five octarepeat regions, a hydrophobic region (113–135), a disulfide bond between its cysteine residues 179 and 214, two N-glycosylation sites (residues 187 and 197), and a GPI anchor at its C-terminal. The structured conformation between amino acids 121 and 231 corresponds to a globular domain, which contains two β-sheets and three α-helices. (A) Linear representation of PrP sequence [modified from Acevedo-Morantes and Wille (2014)]. (B) PrP structure.

FIGURE 2

PrP^C as a signal transducer. In the context of Alzheimer’s disease, the interaction between Aβ oligomers and PrP^C affects receptors located on the plasmatic membrane, such as NMDAR and mGluR5. In the case of NMDAR, because of the interaction of Aβ oligomers and PrP^C, the receptor is phosphorylated through Fyn, hyperactivating the channel and causing glutamatotoxicity. In the case of mGluR5, there is a direct interaction between PrP^C and the receptor, causing the activation of Fyn kinase and promoting the phosphorylation of eEF2 and the consequent loss of neuritic spines.