Summary Prion diseases, or Transmissible Spongiform Encephalopathies (TSE), are neurodegenerative disorders caused by the accumulation of misfolded conformers (PrP Sc ) of the cellular prion protein (PrP C ). During the pathogenesis, the PrP Sc seeds disseminate in the central nervous system and convert PrP C leading 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 PrP Sc structures. In this work, we implemented the recent developments on PrP Sc structural 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.

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