Photodegradation illuminates the role of polyanions in prion infectivity

Abstract

Understanding the mechanism by which prion infectivity is encoded by the misfolded protein PrP Sc remains a high priority within the prion field. Work from several groups has indicated cellular cofactors may be necessary to form infectious prions in vitro. The identity of endogenous prion conversion cofactors is currently unknown, but may include polyanions and/or lipid molecules. In a recent study, we manufactured infectious hamster prions containing purified PrP Sc, co-purified lipid and a synthetic photocleavable polyanion. The polyanion was incorporated into infectious PrP Sc complexes and then specifically degraded by exposure to ultraviolet light. Light-induced in situ degradation of the incorporated polyanion had no effect on the specific infectivity of the samples as determined by end-point dilution sPMCA and scrapie incubation time assays. Furthermore, prion strain properties were not changed by polyanion degradation, suggesting that intact polyanions are not required to maintain the infectious properties of hamster prions. Here, we review these results and discuss the potential roles cofactors might play in encoding prion infectivity and/or strain properties.