Prion Protein and
Transmissible Spongiform Encephalopathies

Prion diseases are characterized by the 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 GPI moiety, see Figure 9. 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 the cellular response to oxidative stress.

Figure 9. 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 and by insolubility in nondenaturing detergents, 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. The formation of PrP^Sc appears to result from the conversion of PrP^C to PrP^Sc through a conformational change in the polypeptide from one with predominantly a-helical secondary structure to one with predominantly b-sheet.

We are currently characterizing at the molecular level the post-translational processing of the prion protein, in particular its intracellular targeting, lipid raft association and proteolytic cleavage. We are also examining the role of PrP^C in neuronal copper metabolism and in the resistance of cells to oxidative stress. The prion-like protein, Doppel, is also being characterised.