Impact of replication and structural diversification of prions on their cerebral dissemination – PrionDif

Prions are lethal proteinaceous pathogens with major public-health risks due to their zoonotic and iatrogenic potential. They are composed of aggregated, misfolded conformers of the host-encoded prion protein that progressively deposit in the brain by a self-perpetuating reaction. The underlying molecular mechanisms of replication and tissue dissemination remain mostly elusive. Our objective is to model these processes entirely based on recent advances that prion aggregates are conformationally heterogeneous and dynamic rather than uniform and static. To achieve this, we will map in prion-infected brain the structural diversification-to-bioactivity/neurotoxicity landscape of prion assemblies in a spatiotemporal manner and mathematically build a multiscale model of diversification and lesion spreading. The goal is to generate an open access model capable of predicting the disease progression and identify key elementary process for therapeutics intervention and early diagnostics.