The biological function of the cellular prion protein: an update

Abstract

The misfolding of the cellular prion protein (PrPC) causes fatal neurodegenerative diseases. Yet PrPC is highly conserved in mammals, suggesting that it exerts beneficial functions preventing its evolutionary elimination. Ablation of PrPC in mice results in well-defined structural and functional alterations in the peripheral nervous system. Many additional phenotypes were ascribed to the lack of PrPC, but some of these were found to arise from genetic artifacts of the underlying mouse models. Here, we revisit the proposed physiological roles of PrPC in the central and peripheral nervous systems and highlight the need for their critical reassessment using new, rigorously controlled animal models.

Transition of the prion protein from a structured cellular form (PrPC) to the infectious scrapie agent (PrPSc)

“…7 The cellular prion protein is expressed almost ubiquitously throughout the human bodily tissues but larger quantities are Abbreviations: NMR, nuclear magnetic resonance spectroscopy; PDB, protein data bank; TSEs, stransmissible spongiform encephalopathies. 15 Functional interactions with PrP C have recently been reported for the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor and the N-methyl-D-aspartate glutamate receptor, as well as the Type 1 metabotropic glutamate receptors mGluR1 and mGluR5. The only function of PrP C that is well-understood at the molecular level is its role as the physiological ligand of the G protein-coupled receptor, Gpr126.…”

“…14 PrP C is increasingly being recognized as a promiscuous regulator of neuronal signaling; PrP C has been shown to interact with, and to modulate, a surprisingly large number of membrane receptors, including ionotropic and metabotropic glutamate receptors, ion channels, and amino acid transporters. 15 Functional interactions with PrP C have recently been reported for the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor and the N-methyl-D-aspartate glutamate receptor, as well as the Type 1 metabotropic glutamate receptors mGluR1 and mGluR5. [16][17][18] In addition, PrP C has been shown to regulate glutamate uptake by the excitatory amino acid transporter EAAT3 that further supports it's active role in neurotransmission and protection from excitotoxicity.…”

Prion protein—Semisynthetic prion protein (PrP) variants with posttranslational modifications

“…[116][117][118] A more detailed discussion can be found in reviews by the group of Aguzzi. 109,119 Recently, other functions have been attributed to PrP C , that is acting as a receptor for the aggregated proteins Aβ oligomers [120][121][122] and α-synuclein. 123 By mediating the uptake of Aβ and α-synuclein, PrP Sc is unable to replicate in their presence.…”

Sensing α‐Synuclein From the Outside via the Prion Protein: Implications for Neurodegeneration

“…The normal physiological function of PrP C is still a subject of debate . PrP C is a glycosylphosphatidylinositol‐anchored cell‐surface protein encoded by the Prnp gene and is highly expressed throughout the central nervous system in neurons and astrocytes .…”

“…PrP C modulates phosphorylation cascades via Fyn kinase, a member of the Src tyrosine kinase family highly expressed in neuronal cells . Previous studies described the activation of Fyn by PrP C , related to their localization in lipid rafts at the postsynaptic density .…”