Quaternary structural convergence and structural diversification of prion assemblies at the early replication stage

Abstract

AbstractAggregation of misfolded forms from host-encoded proteins is key to the pathogenesis of a number of neurodegenerative disorders, including prion diseases, Alzheimer’s disease and Parkinson’s disease. In prion diseases, the cellular prion protein PrPCcan misfold into PrPScand auto-organize into conformationally distinct assemblies or strains. A plethora of observations reports the existence of PrPScstructural heterogeneity within prion strains, suggesting the emergence and coevolution of structurally distinct PrPScassemblies during prion replication in controlled environment. Such PrPScdiversification processes remain poorly understood. Although central to prion host-adaptation, structural diversification of PrPScassemblies is also a key issue for the formation of PrP conformers involved in neuronal injury. Here, we characterized the evolution of the PrPScquaternary structure during prion replicationin vivoand inbona fidecell-free amplification assays. Regardless of the strain studied, the early replication stage conduced to the preferential formation of small PrPScoligomers, thus highlighting a quaternary structural convergence phenomenon. Their evolutionary kinetics revealed the existence of a PrPC-dependent secondary templating pathway in concert with a structural rearrangement. This secondary templating pathway provides, for the first time, a mechanistic explanation for prion structural diversification during replication, a key determinant for prion adaptation on further transmission, including to other host species. The uncovered processes are also key for a better understanding of the accumulation mechanisms of other misfolded assemblies believed to propagate by a prion-like process.