Abstract
Prion diseases, or transmissible spongiform encephalopathies (TSEs), are fatal neurodegenerative disorders caused by the accumulation of misfolded conformers (PrPSc ) of the cellular prion protein (PrPC ). These pathogenic assemblies propagate through a self-templating process, resulting in strain- specific patterns of neurodegeneration, yet the mechanisms underlying their tissue tropism and dissemination remain incompletely understood. Using advanced physico-chemical approaches, we revealed that PrP Sc assemblies exhibit an intrinsic capacity for structural diversification and material exchange, independently of templated replication. These findings challenge traditional paradigms by suggesting that prion replication is not solely governed by templating kinetics, but also shaped by inherent assembly dynamics. Building on this foundation, we incorporated these experimental observations into a stochastic reaction-diffusion model—parametrized with the Gillespie algorithm—that accounts for nonlinear tissue responses, particularly the unfolded protein response (UPR), and strain-specific replication kinetics. This integrated framework demonstrates that the interplay between the intrinsic dynamics of prion assemblies and tissue feedback mechanisms can lead to diverse replication regimes, including oscillatory, transient, and abortive behaviors. Notably, the model reveals that structural subpopulations such as PrPSc A and PrPSc Bi can be differentially selected depending on tissue environment and strain properties. Furthermore, strain co-propagation and dominance interference are emergent behaviors resulting from shared substrate competition and UPR coupling, independent of direct kinetic interaction. By simulating prion dissemination across neural networks, the model also underscores the role of the brain’s connectome—not as a passive conduit, but as an active modulator of propagation dynamics through axon-guided diffusion and local replication. Together, these insights offer a comprehensive and mechanistically rich model of prion replication and neuroinvasion, with broader implications for other protein misfolding diseases characterized by strain diversity and tissue tropism.