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

Prion diseases, or transmissible spongiform encephalopathies (TSEs), 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.