The double life of the prion protein

Abstract

The function of the cellular prion protein PrPC, which is anchored to the cell-surface by a glycolipid attachment, is unknown. Its sequence is highly conserved, which usually implies that a protein has some important function. But the mild phenotype observed in some PrP knockout mice — reduced long-term potentiation of synaptic transmission, which is normally associated with learning, and sleep pattern abnormalities — suggests that whatever the normal role of PrPC, it can be at least partially fulfilled by other proteins.Point mutations in the PrP gene can lead to inherited human neurological diseases which resemble transmissible scrapie, such as Creutzfeldt–Jakob disease, Gerstmann–Straussler–Scheinker disease and fatal familial insomnia. It is difficult to understand why a gene sequence that is only a single mutation away from protein aggregation and neurological disaster should be conserved. We propose a solution to this paradox. The normal function of PrPC may require its controlled oligomerization under conditions which prevent the uncontrolled polymerization that would lead to PrPSc formation. The oligomerized normal protein could be involved in cell–cell interactions, synapse formation or membrane protein recycling. The elucidation of this normal function could hold the key to understanding the pathogenesis of scrapie and related spongiform encephalopathies.