THE DYNAMICS AND MISFOLDING PATHWAYS OF THE PRION PROTEIN AT ATOMIC RESOLUTION

Abstract

Prion diseases are fatal, transmissible and incurable neurodegenerative diseases that only infect mammals. While the manifestation of prion disease is not completely understood, it is known that the prion protein (PrP) plays a critical role in prion disease development. The PrP can exist in two different isoforms: PrPC is the native cellular form which is innocuous, while PrPSc is the pathogenic form. PrPSc is aggregation-prone thus forming soluble oligomers which are toxic and infectious. Using molecular dynamics simulations, we have investigated misfolding pathways for human PrP pathogenic mutants and bovine PrP at acidic pH. In order to better understand the molecular dynamics of the PrPC at a physiological environment, we have also performed simulations of the human PrPC attached with glycans in a membrane environment, revealing protective mechanisms against misfolding. Using recent experimental data on PrPSc soluble oligomers, we have validated our current structural model for PrPSc oligomers and finally, combining our findings from both bovine PrPSc and human PrPC, we have constructed a system to model the PrPSc-induced misfolding for the human PrPC in a physiological environment. Our research sheds light on the PrP misfolding mechanism at the atomic level, potentially advancing future therapeutic and diagnostic development on prion diseases.