Aggregation Propensity of Prion is Kinetically Controlled by Intramolecular Diffusion of Protein Chain

Abstract

Prion disease are rapidly progressive neurodegenerative disorders like Alzheimer's disease and Parkinson disease that are attributed to misfolding followed by ordered aggregation and accumulation of protein deposits in neuronal cells. According to the “protein only” hypothesis, the central event in prion pathogenesis is the conformational conversion of the cellular α-helical rich isoform, PrPC, into misfolded β-sheet rich isoform, PrPSc. Here we present a novel way to understand the molecular basis of Prion misfolding and aggregation, by investigating the early stage intramolecular backbone reconfiguration of monomer. Our hypothesis is that when reconfiguration is much faster or much slower than bimolecular diffusion, biomolecular association is not stable, but as the reconfiguration rate becomes similar to the rate of biomolecular diffusion, the association is more stable and subsequent aggregation is faster. We are investigating the effects of reducing agent, pH and denaturant on reconfiguration dynamics of the Hamster and Rabbit Prion protein. This work not only provides a better understanding of early stage conformational dynamics, but also provides a way forward for a novel therapeutic strategy of drug development which can bind monomers and prevent aggregation at the earliest step.