Heterogeneity and Architecture of Pathological Prion Protein Assemblies: Time to Revisit the Molecular Basis of the Prion Replication Process?

Abstract

Prions are proteinaceous infectious agents responsible for a range of neurodegenerative diseases in animals and humans. Prion particles are assemblies formed from a misfolded, β-sheet rich, aggregation-prone isoform (PrPSc) of the host-encoded cellular prion protein (PrPC). Prions replicate by recruiting and converting PrPC into PrPSc, by an autocatalytic process. PrPSc is a pleiomorphic protein as different conformations can dictate different disease phenotypes in the same host species. This is the basis of the strain phenomenon in prion diseases. Recent experimental evidence suggests further structural heterogeneity in PrPSc assemblies within specific prion populations and strains. Still, this diversity is rather seen as a size continuum of assemblies with the same core structure, while analysis of the available experimental data points to the existence of structurally distinct arrangements. The atomic structure of PrPSc has not been elucidated so far, making the prion replication process difficult to understand. All currently available models suggest that PrPSc assemblies exhibit a PrPSc subunit as core constituent, which was recently identified. This review summarizes our current knowledge on prion assembly heterogeneity down to the subunit level and will discuss its importance with regard to the current molecular principles of the prion replication process.

Complementation between pathological prion protein subassemblies to cross existing species barriers

“…For LA21K fast and 127S strains, a discrete population of small oligomers (<pentamers) exhibit the highest specific infectivity values. For LA19K, the highest specific infectivity values are associated with larger-size oligomers (>40 PrP-mers) [23]. We also included atypical L-BSE prions in the study, because of their mutability on cross-species transmission [37].…”

“…LA21K fast prions are composed of at least two structurally PrP Sc subsets in different proportion, each with distinct specific infectivity [23,15,18]. Dilution experiments constitute a relevant method to explore the contribution of each PrP Sc subtype.…”

“…Size-fractionation studies by sedimentation velocity (SV) indicate that variability in PrP Sc quaternary structure is strain-specific [15,18,17,21,22]. Within a given prion strain, PrP Sc assemblies with differing quaternary structure exhibit markedly different templating and biological activities, which are a hallmark of the existence of structurally distinct PrP Sc subpopulations, as previously discussed [23]. The biological and biochemical consequences of PrP Sc structural heterogeneity during prion replication and propagation are poorly understood.…”

An alternative model to prion fragmentation based on the detailed balance between PrPScand suPrP

“…Recent work demonstrated the existence of a constitutional detailed balance between PrP Sc assemblies and an oligomeric conformer called suPrP. The latter constitutes the elementary building block of PrP Sc assemblies [9,10] (Figure 1.2a). The existence of a detailed balance between PrP Sc and suPrP makes the quaternary structure of prion assemblies highly dynamic in contrast with the widespread deadpan vision of amyloid assemblies.…”

“…According to the detailed balance process between PrP Sc and suPrP, during prion replication the consumption of monomeric PrP C also contributes to the increase of suPrP quantity (Figure 1.2b). This suPrP leakage could circumvent the necessity of fragmentation to amplify the templating interface [9]. Therefore, in the present work we explore the existence of the detailed balance between PrP Sc and suPrP as an alternative process to the fragmentation to couple the linear templating process and templating interface amplification.…”