Structural Dynamics and Kinetic Interplay in Prion Assembly

Introduction:
The prion pathology is based on autonomous structural information propagation towards single or multiple protein conformational changes. The unified theory in Prion replication implies structural information transference from the prion to a non-prion conformer through a mechanism also called improperly, with regards to biophysical considerations, “seeding” phenomenon.  A plethora of data reported in the literature highlights the existence of multiple structurally distinct subassemblies within a single strain, indicating that during the replication process, multiple conformations can emerge. The coexistence of these structurally different prion assemblies raises important questions about how they are maintained within the same environment and how they escape selection by the most efficient replicator.

Objectives:
To explore the dynamic nature of these subassemblies and determine how structurally distinct prion assemblies co-evolve within the same environment.

Methods:
Using approaches including single-molecule techniques like high-resolution liquid atomic force microscopy (AFM), and colligative methods like time-resolved static light scattering (SLS), the dynamics of synthetic Bank Vole prions and brain-derived assemblies were investigated.

Results:
Structural characterization of Bank Vole and 263K prion assemblies by AFM revealed the presence of multiple structural subtypes. Notably, an asymmetric release of oligomers from fibrils was observed. Dynamic analysis using static light scattering (SLS) showed a time-dependent decrease in mean molecular size, indicating a depolymerization trend.

Conclusion:
Prion assemblies are highly dynamic and far from equilibrium. A complex exchange process occurs between prion subpopulations. An autocatalytic depolymerization mechanism was identified. These nonlinear dynamics offer new research opportunities.