At least five different scenarios can be proposed for the involvement of cellular co-factors in prion propagation. i, The co-factor might integrate into the infectious agent, alter PrP^Sc folding and provide biological information to the infectivity process, perhaps by determining strain characteristics. ii, The co-factor might act as an essential catalyst for prion replication, perhaps by interacting with PrP^C, altering its folding and permitting its interaction with PrP^Sc. iii, Through binding and integration into the PrP^Sc polymer, the co-factor might help to stabilize the conformation of PrP^Sc. iv, The co-factor might participate in the key process of fragmenting PrP^Sc polymers to produce smaller structures and multiplying the number of seeds to allow the continuation of prion replication. v, The co-factor might bind to PrP^Sc, thus increasing its biological stability, reducing its clearance in vivo and increasing its chances to reach target organs. It is important to highlight that these possibilities are not mutually exclusive and indeed, it is likely that a co-factor could be involved in several of these processes simultaneously.

Starting with the initial indication that prion diseases can be transmissible, owing to the accidental transmission of scrapie in sheep and ending with the demonstration that infectious material can be generated in vitro using pure recombinant prion protein, the prion field has always been full of unorthodox discoveries.