Abstract

Misfolding of prion protein (PrP) into amyloid aggregates is the central feature of prion diseases. PrP has an amyloidogenic C-terminal domain with three α-helices and a flexible tail in the N-terminal domain in which multiple octapeptide repeats are present in most mammals. The role of the octapeptides in prion diseases has previously been underestimated because the octapeptides are not located in the amyloidogenic domain. Correlation between the number of octapeptide repeats and age of onset suggests the critical role of octapeptide repeats in prion diseases. In this study, we have investigated four PrP variants without any octapeptides and with 1, 5 and 8 octapeptide repeats. From the comparison of the protein structure and the thermal stability of these proteins, as well as the characterization of amyloids converted from these PrP variants, we found that octapeptide repeats affect both folding and misfolding of PrP creating amyloid fibrils with distinct structures. Deletion of octapeptides forms fewer twisted fibrils and weakens the cytotoxicity. Insertion of octapeptides enhances the formation of typical silk-like fibrils but it does not increase the cytotoxicity. There might be some threshold effect and increasing the number of peptides beyond a certain limit has no further effect on the cell viability, though the reasons are unclear at this stage. Overall, the results of this study elucidate the molecular mechanism of octapeptides at the onset of prion diseases.

Highlights

  • Transmissible spongiform encephalopathies (TSE or prion diseases) are fatal neurodegenerative disorders with sporadic, infectious and inherited etiologies

  • The Number of Octapeptide Repeats Affects the Structure and the Thermal Stability of According to the Nuclear magnetic resonance (NMR) studies, prion proteins (PrP) is rich with α-helices located in the C-terminal domain, while the N-terminal domain is unstructured [7]

  • Extensive studies of recombinant prion proteins indicate that PrP90–231 can poten3

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Summary

Introduction

Transmissible spongiform encephalopathies (TSE or prion diseases) are fatal neurodegenerative disorders with sporadic, infectious and inherited etiologies. The prion proteins (PrP) play an essential role in the pathogenesis of prion diseases. According to the proteinonly hypothesis [1], the normal cellular isoform of the prion protein (PrPC ) misfolds and aggregates into a disease-associated state termed PrPSc (Sc stands for Scrapie) [2]. PrPC is sensitive to protease K (PK)-digestion, while PrPSc is resistant to PK-digestion. PrPC is ubiquitous throughout the central nervous system of mammals [3]. Misfolding of PrPC into PrPSc readily causes various types of transmissible spongiform encephalopathies in animals, such as Creutzfeldt-Jakob disease (CJD) in humans, bovine spongiform encephalopathy (BSE) in cattle and Scrapie in sheep.

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