Prion diseases are fatal and currently untreatable neurodegenerative diseases of humans and animals. The central event underlying these diseases is the 3D conversion of the prion protein (PrPC) to a pathogenic shape, denoted PrPSc. It is often said that to understand a person, one should look at the company they keep. This is also true of proteins, as their interaction networks, or interactomes, define their functions. Although some information is available about the cellular partners of PrPC, almost nothing is known about the interaction network of PrPSc. Here, we propose to examine the PrPSc interactome for the first time, providing a wealth of new targets for therapeutic intervention.