Mechanisms of strain diversity of disease-associated in-register parallel β-sheet amyloids and implications about prion strains

Abstract

18The mechanism of strain diversity of prions still remains unsolved, because the investigation of inheritance and 19 diversification of the protein-based pathogenic information demands identification of the detailed structures of abnormal 20 isoform of prion protein (PrP Sc ), while it is difficult to purify for analysis without affecting the infectious nature. On the other 21 hand, the similar prion-like properties are recognized also in other disease-associated in-register parallel β -sheet amyloids 22 including Tau and α -synuclein (αSyn) amyloids. Investigations into structures of those amyloids by solid-state nuclear 23 magnetic resonance spectroscopy and cryo-electron microscopy recently made remarkable advances, because of their 24 relatively small sizes and lack of post-translational modifications. We review the advances on those pathogenic amyloids, 25 particularly Tau and α Syn, and discuss their implications about strain diversity mechanisms of prion/PrP Sc from the 26 viewpoint that PrP Sc is an in-register parallel β -sheet amyloid. We also present our recent data of molecular dynamics 27 simulations of α Syn amyloid, which suggest significance of compatibility between β -sheet propensities of the substrate and 28 local structures of the template for stability of the amyloid structures. Detailed structures of the α Syn and Tau amyloids are 29 good surrogate models of pathogenic amyloids including PrP Sc to elucidate not only the strain diversity but also their 30 pathogenic mechanisms. 31 32 33Strain diversity is one of the most mysterious feature of prions. The strain-specific traits of prions are enciphered in 34 the structures of the abnormal isoform prion protein (PrP Sc ), and they are stably inherited over generations solely by 35 passaging the exact structures of the PrP Sc through template-directed refolding of the normal isoform prion protein (PrP C ), 36 where the template PrP Sc imprint the structural details onto the substrate PrP C . Moreover, the strain-specific pathogenic 37 information encoded in the conformation of the PrP Sc is reproducibly "translated" into the strain-specific clinicopathological 38 traits in the manifested diseases [1] [2]. This view is widely accepted as the protein-only hypothesis but detailed 39 mechanisms, e.g., specifically what structures of PrP Sc encodes the pathogenic information and how the information is 40 translated, remain a challenge to the current biology. Investigations of the storage, inheritance and diversification of the 41 protein-based pathogenic information demand identification of the structure-phenotype correlations, but it is very difficult 42 because detailed structures of the entire PrP Sc is not available yet due to its incompatibility with high-resolution structural 43 analyses, i.e., X-ray crystallography or nuclear magnetic resonance spectrometry (NMR). The incompatibility is attributable 44 to difficulty in purification without losing infectivity [3], difficulty in recapitulating bona fide prion...

Conformation-dependent influences of hydrophobic amino acids in two in-register parallel β-sheet amyloids, an α-synuclein amyloid and a local structural model of PrPSc

“…In contrast, αSyn(G84L) and αSyn(G84V) amyloids only infrequently showed that pattern or were similar to those of another destabilizing mutation, G84I. 28 This result was reflected in the distance between residues 84 and 89. The C α -C α distances (dC α ) between the residues 84 and 89 were about 8.3Å in all the chains during the simulations of αSyn(G84M), whereas the distances varied among chains and fluctuated in αSyn(G84L), αSyn(G84V), and αSyn(G84I) (Figure S1).…”

“…We thus used an in-register parallel β -sheet amyloid of α -synuclein ( α Syn) as a surrogate local structural model for PrP Sc , as in our previous studies. 28,29…”

Temperature-Dependent Structural Variability of Prion Protein Amyloid Fibrils

“…Amyloidogenic protein aggregation into insoluble, beta-sheet rich fibrils is linked with the onset of several neurodegenerative disorders, such as Alzheimer’s, Parkinson’s or prion diseases [ 1 , 2 ]. The way these structures form and propagate is still not fully understood, as evidence for new aggregation mechanisms or fibril structural features [ 3 , 4 , 5 ] keeps appearing on a regular basis. This lack of crucial information is likely one of the factors that has led to countless failed clinical trials [ 6 ] and to only a handful of effective, disease-modifying drugs [ 7 ].…”

Formation of distinct prion protein amyloid fibrils under identical experimental conditions

“…There has been an ongoing effort to not only differentiate 36 , but to purify strains of prion protein fibrils 37 . However, as of yet, single strain purification is still difficult 38 .…”