Self-Replication of Prion Protein Fragment 89-230 Amyloid Fibrils Accelerated by Prion Protein Fragment 107-143 Aggregates.

Tomas Sneideris,Brett K.-Y Chu,Rita P.-Y Chen,Vytautas Smirnovas,Mantas Ziaunys

doi:10.3390/ijms21197410

Abstract

Prion protein amyloid aggregates are associated with infectious neurodegenerative diseases, known as transmissible spongiform encephalopathies. Self-replication of amyloid structures by refolding of native protein molecules is the probable mechanism of disease transmission. Amyloid fibril formation and self-replication can be affected by many different factors, including other amyloid proteins and peptides. Mouse prion protein fragments 107-143 (PrP(107-143)) and 89-230 (PrP(89-230)) can form amyloid fibrils. -sheet core in PrP(89-230) amyloid fibrils is limited to residues ∼160–220 with unstructured N-terminus. We employed chemical kinetics tools, atomic force microscopy and Fourier-transform infrared spectroscopy, to investigate the effects of mouse prion protein fragment 107-143 fibrils on the aggregation of PrP(89-230). The data suggest that amyloid aggregates of a short prion-derived peptide are not able to seed PrP(89-230) aggregation; however, they accelerate the self-replication of PrP(89-230) amyloid fibrils. We conclude that PrP(107-143) fibrils could facilitate the self-replication of PrP(89-230) amyloid fibrils in several possible ways, and that this process deserves more attention as it may play an important role in amyloid propagation.

Highlights

Several neurodegenerative human health disorders, such as Alzheimer’s disease (AD) [1], Parkinson’s disease (PD) [2], as well as prion diseases [3] are all closely linked to a process, where particular proteins fail to maintain their native conformational state and form fibrillar amyloid aggregates possessing a cross-β structure
The aggregation reaction did not occur within reasonable experimental time (Appendix A Figure A2), the experimental conditions were modified to obtain rapid fibril elongation kinetics [34]
The addition of high amounts (10%) of PrP(107-143) fibrils into PrP(89-230) monomer solution had no effect on aggregation kinetics within the experimental time, whereas addition of even very low amounts (0.1%) of PrP(89-230) fibrils resulted in a substantial acceleration of aggregation reaction (Figure 1a,b)

Summary

Introduction

Several neurodegenerative human health disorders, such as Alzheimer’s disease (AD) [1], Parkinson’s disease (PD) [2], as well as prion diseases [3] are all closely linked to a process, where particular proteins fail to maintain their native conformational state and form fibrillar amyloid aggregates possessing a cross-β structure. There are no cures or disease-modifying drugs available for most of these disorders, and even compounds that show promising results in vitro experience very high failure rates during clinical trials [4,8,9,10] Analysis of such failures revealed that the main factors preventing successful development of effective anti-amyloid drugs are the relatively poor understanding of amyloid aggregation mechanisms; the lack of knowledge of the specific species and aggregation step(s) that may be affected by the molecule in question; the lack of methods to monitor the aggregation reaction in a reliable manner [4,11]. There are two defined events related with amyloid fibril self-replication: fibril elongation and fibril surface-catalyzed nucleation (often referred to as secondary nucleation) [4,12,13,14,15]. Elongating fibrils usually replicate the structure of the initial seed (with only a couple of exceptions of possible conformational switching reported [16,17]); there is increasing evidence suggesting that the structure of amyloid fibrils replicated via secondary nucleation route is dependent on the environment rather than on the template of seeds [18,19,20,21]

Methods

Results

Conclusion