The function of the cellular prion protein in health and disease

Abstract

The essential role of the cellular prion protein (PrP^C) in prion disorders such as Creutzfeldt-Jakob disease is well documented. Moreover, evidence is accumulating that PrP^C may act as a receptor for protein aggregates and transduce neurotoxic signals in more common neurodegenerative disorders, such as Alzheimer's disease. Although the pathological roles of PrP^C have been thoroughly characterized, a general consensus on its physiological function within the brain has not yet been established. Knockout studies in various organisms, ranging from zebrafish to mice, have implicated PrP^C in a diverse range of nervous system-related activities that include a key role in the maintenance of peripheral nerve myelination as well as a general ability to protect against neurotoxic stimuli. Thus, the function of PrP^C may be multifaceted, with different cell types taking advantage of unique aspects of its biology. Deciphering the cellular function(s) of PrP^C and the consequences of its absence is not simply an academic curiosity, since lowering PrP^C levels in the brain is predicted to be a powerful therapeutic strategy for the treatment of prion disease. In this review, we outline the various approaches that have been employed in an effort to uncover the physiological and pathological functions of PrP^C. While these studies have revealed important clues about the biology of the prion protein, the precise reason for PrP^C's existence remains enigmatic.