Abstract
The mechanism of prion strain diversity remains unsolved. Investigation of inheritance and diversification of protein-based pathogenic information demands the identification of the detailed structures of abnormal isoforms of the prion protein (PrPSc); however, achieving purification is difficult without affecting infectivity. Similar prion-like properties are recognized also in other disease-associated in-register parallel β-sheet amyloids including Tau and α-synuclein (αSyn) amyloids. Investigations into structures of those amyloids via solid-state nuclear magnetic resonance spectroscopy and cryo-electron microscopy recently made remarkable advances due to their relatively small sizes and lack of post-translational modifications. Herein, we review advances regarding pathogenic amyloids, particularly Tau and αSyn, and discuss implications about strain diversity mechanisms of prion/PrPSc from the perspective that PrPSc is an in-register parallel β-sheet amyloid. Additionally, we present our recent data of molecular dynamics simulations of αSyn amyloid, which suggest significance of compatibility between β-sheet propensities of the substrate and local structures of the template for stability of amyloid structures. Detailed structures of αSyn and Tau amyloids are excellent models of pathogenic amyloids, including PrPSc, to elucidate strain diversity and pathogenic mechanisms.
Highlights
Strain diversity is one of the most mysterious features of mammalian prions
After of amyloids are unveiled, question to 4B, be addressed is β-sheet propensities of strain-specific this region arestructures not necessarily high because of coilthe propensity
The left), the conformation of native PrP possibly restricts the mobility of H1~H2 region to make it induction of conformational changes by pathogenic amyloids propensity
Summary
Strain diversity is one of the most mysterious features of mammalian prions. The strain-specific traits of prions are enciphered in the structures of the abnormal isoform prion protein (PrPSc ), and they are stably inherited over generations through template-directed refolding of the normal isoform prion protein (PrPC ), where the template PrPSc imprints the structural details onto the substrate. The primary structures might be significant determinants of positions of β-sheets in in-register parallel amyloids, Consistent with different patterns of the cross-β spines, Pick’s form and the AD form of Tau amyloids showed different proteolytic-fragment patterns on immunoblots after trypsin digestion [31]. In-vitro formed αSyn fibrils showed at least two types of morphologically-distinguishable strains, “ribbon” and “fibril” types, which are different in dimensions of the fibrils, blotting patterns of protease-resistant fragments, cytotoxicity, and optimal salt conditions for efficient in-vitro propagation [49,50] Their secondary structures determined by ssNMR revealed strain-specific β-sheet distributions: the ribbon had stable β-sheet structures in the N-terminal region encompassing residues 1–38, whereas the corresponding region of the fibril type was disordered except for a short β-sheet 16–20.
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