Abstract:

The prion protein (PrP), through misfolding, is widely known for its causative role in prion diseases, which are transmissible neurodegenerative diseases of humans and animals. There is still no defined function assigned to PrP, especially in the central nervous system, despite many studies in this area. Proposed functions are protean and include signal transduction, neuroprotection, neurogenesis, neuritogenesis, metal-ion homeostasis, memory formation and consolidation, as well as circadian rhythms. Part of the difficulty in assigning aspecific function to PrP could perhaps be that it does not have one single function. Instead it might be able to perform many functions and influence various pathways depending upon contextual post-translational modification. Recently a further cleavage event has been extensively characterised. Referred to as “gamma-cleavage”, this event occurs in the C-terminal structured domain and therefore produces fragments with very different features to both the α- and β-cleavages. A functional significance is yet to be assigned to this processing event, but its presence in multiple cells and tissues, and in disease, suggests that the fragments produced are likely toexert cellular effects distinct to that produced by the other PrP constitutive processing events. The precise cellular locations of the cleavage events and of the resulting fragments, whether processing occurs at the cell surface and whether N-terminal fragments act in cis or trans, the enzymes controlling these events, the membrane micro-milieuand dynamic rather than absolute cleavage levels may all potentially impact functional consequences. Until the various nuances of combined post-translational modifications of PrP coupled with cleavage events in different contexts and in different tissues are fully elucidated, PrP appears destined to remain an enigmatic “actor” playing in many apparent functional roles.