Early stage prion assembly involves two subpopulations with different quaternary structures and a secondary templating pathway

Angélique Igel-Egalon,Fabienne Reine,Christelle Jas-Duval,Marie Doumic,Laetitia Herzog,Tina Knäpple,Human Rezaei,Florent Laferrière,Mathieu Mezache,Mohammed Moudjou,Vincent Béringue,Jan Bohl

doi:10.1038/s42003-019-0608-y

Abstract

The dynamics of aggregation and structural diversification of misfolded, host-encoded proteins in neurodegenerative diseases are poorly understood. In many of these disorders, including Alzheimer’s, Parkinson’s and prion diseases, the misfolded proteins are self-organized into conformationally distinct assemblies or strains. The existence of intrastrain structural heterogeneity is increasingly recognized. However, the underlying processes of emergence and coevolution of structurally distinct assemblies are not mechanistically understood. Here, we show that early prion replication generates two subsets of structurally different assemblies by two sequential processes of formation, regardless of the strain considered. The first process corresponds to a quaternary structural convergence, by reducing the parental strain polydispersity to generate small oligomers. The second process transforms these oligomers into larger ones, by a secondary autocatalytic templating pathway requiring the prion protein. This pathway provides mechanistic insights into prion structural diversification, a key determinant for prion adaptation and toxicity.

Highlights

The dynamics of aggregation and structural diversification of misfolded, host-encoded proteins in neurodegenerative diseases are poorly understood
The early phases of prion replication are commonly thought to consist of an elongation process[40], with the PrPSc template serving as a base
No proteinase K (PK)-resistant PrPSc (PrPres) was detected in the brain of vCJD inoculated PrP knock-out mice (PrP−/−) analysed for PrPres content at early time points (Supplementary Fig. 3)

Summary

Introduction

The dynamics of aggregation and structural diversification of misfolded, host-encoded proteins in neurodegenerative diseases are poorly understood In many of these disorders, including Alzheimer’s, Parkinson’s and prion diseases, the misfolded proteins are selforganized into conformationally distinct assemblies or strains. The autocatalytic conversion model proposed by Griffith in 196731, the nucleated-polymerization model described by Lansbury and Caughey in 199532 and other derived models (e.g.33) merely assume the existence of structurally homogenous assemblies that have absolutely identical propensity to replicate throughout disease progression These mechanisms intrinsically reduce PrPSc heterogeneity due to the best replicator selection process[34,35,36]. To examine the molecular mechanisms of PrPSc replication and structural diversification, we explore, by sedimentation velocity (SV)-based methods, the quaternary structure evolution of PrPSc assemblies during the early stage of prion conversion in vivo and in a cell-free system by protein misfolding cyclic amplification[39]

Methods

Results

Conclusion