The dynamics of prion spreading is governed by the interplay between the non-linearities of tissue response and replication kinetics

Abstract

SummaryPrion diseases, or Transmissible Spongiform Encephalopathies (TSE), are neurodegenerative disorders caused by the accumulation of misfolded conformers (PrPSc) of the cellular prion protein (PrPC). During the pathogenesis, the PrPScseeds disseminate in the central nervous system and convert PrPCleading to the formation of insoluble assemblies. As for conventional infectious diseases, variations in the clinical manifestation define a specific prion strain which correspond to different PrPScstructures. In this work, we implemented the recent developments on PrPScstructural diversity and tissue response to prion replication into a stochastic reaction-diffusion model using an application of the Gillespie Algorithm. We showed that this combination of non-linearities can lead prion propagation to behave as a complex system, providing an alternative to the current paradigm to explain strain specific phenotypes, tissue tropisms and strain co-propagation while also clarifying the role of the connectome in the neuro-invasion process.