The structural line between prion and "prion-like": Insights from prion protein and tau

Abstract

The concept of 'prion-like' behavior has emerged in the study of diseases involving protein misfolding where fibrillar structures, called amyloids, self-propagate and induce disease in a fashion similar to prions. From a biological standpoint, in order to be considered 'prion-like,' a protein must traverse cells and tissues and further propagate via a templated conformational change. Since 2017, cryo-electron microscopy structures from patient-derived 'prion-like' amyloids, in particular tau, have been presented and revealed structural similarities shared across amyloids. Since 2021, cryo-EM structures from prions of known infectivity have been added to the ex vivo amyloid structure family. In this review, we discuss current proposals for the 'prion-like' mechanisms of spread for tau and prion protein as well as discuss different influencers on structures of aggregates from tauopathies and prion diseases. Lastly, we discuss some of the current hypotheses for what may distinguish structures that are 'prion-like' from transmissible prion structures.

Figure 1. Mechanisms of prion and prion-like amplification.

Prion and prion-like amyloids share a general mechanism of amplification. Amplification via primary nucleation takes place by addition of identical layers of protein building blocks onto the fibril ends that allow for complementary stacking and hydrogen bond formation along the primary growth axis. Secondary nucleation may also take place, whereby new monomers template onto the side of fibrils via side chain interactions to form steric zippers. These mechanisms are represented as a Lego cartoon (left) and further detailed by a peptide fibril example (right).

Figure 2. Secondary structure alignment of disease-derived tau fibrils.

All patient-derived tau fibril structures share common beta sheet structures connected by turns at specific residues regardless of isoform composition. Inspired by Zhang et al. [48].

Figure 3. Structures of disease-associated tau fibrils.

Tauopathies with aggregates sharing isoform composition (3R only, 3R and 4R, and 4R only) share structural similarity. For 4R tauopathies, structures can be classified into two categories based on the number of beta sheet layers making up the core. Beta strands (arrows) from R1 are shown in purple, R2 in blue, R3 in pale teal, R4 in light pink, and the region C-terminal to the repeats in magenta haze. Unassigned densities observed in cryo-EM maps are shown as black solid ellipses. Inspired by figure 3 from Shi et al., 2021 [43].

Figure 4. Tissue-derived prion structures and their passage history.

a) Sequence alignment between the origin species of scrapie prions (sheep) and mammals passaged through to result in particular strains. Human sequence included for GSS, where there is no passage through other hosts. Sequences are numbered according to the human prion protein sequence. b) Passage history of prion strains with structures determined by cryo-EM (263K [57], RML [58], aRML [59], a22L [60], ME7 [64], and GSS [62]. The N-terminal lobe (light blue), C-terminal lobe (brown), extreme N-terminal region (dark blue), and β2α2 loop (tan) which links N- and C-terminal lobes are highlighted in each structure. Residue numbering is converted to the equivalent human prion protein numbering. Inspired by figure 9 from Glynn et al., 2022 [63].