Prion Protein and Transmissible Spongiform Encephalopathies

Prion diseases are characterized by the conformational conversion of the normal cellular form of the prion protein (PrP^C) into an insoluble, protease-resistant abnormal form (PrP^Sc). PrP^C is a glycoprotein anchored to the cell surface by a glycosyl-phosphatidylinositol (GPI) moiety (Figure 3). Although PrP^C is expressed in all mammalian species examined and is highly conserved between species, its role in normal cellular function remains elusive. The available evidence, including the study of PrP knockout mice, suggests that PrP^C is essential for the maintenance of neuronal integrity in the brain, possibly with a role in copper metabolism and/or the cellular response to oxidative stress.

Figure 3. Schematic of the normal cellular form of the prion protein (PrP^C) showing its GPI membrane anchor, the two N-linked glycans and the octapeptide repeats that bind metal ions.

The aberrant isoform of PrP, PrP^Sc, which is characterized by relative resistance to proteolysis, is a hallmark of the prion diseases. These include the familial, transmitted and sporadic forms of neurodegenerative disorders such as Creutzfeldt-Jakob disease, Gerstmann-Straussler-Scheinker syndrome, kuru and fatal familial insomnia in humans, and scrapie and bovine spongiform encephalopathy in animals.
We are currently characterizing at the cellular level the post-translational processing of the prion protein, in particular its lipid raft association, mechanism of endocytosis (Figure 4) and its proteolytic cleavage. We are also examining the role of PrP^C in neuronal copper metabolism and in the resistance of cells to oxidative stress (Figure 5).

Figure 4. Schematic showing the mechanism of endocytosis of PrP^C. PrP^C is located in cholesterol-rich lipid rafts in the plasma membrane. On binding Cu²⁺ it dissociates from the rafts and moves laterally into non-raft regions of the plasma membrane. The N-terminal polybasic region then interacts with a transmembrane adaptor which facilitates the endocytosis of PrP^C through clathrin coated pits.

Figure 5. The role of PrP^C in the cellular response to oxidative stress. (A) Upon exposure of cells to reactive oxygen species (ROS) cell-surface PrP^C is cleaved to generate two fragments N2 and C2. (B) In mutant forms of PrP which are unable to fragment to form N2 and C2 the cellular response to oxidative stress is compromised.