Research Article: The mechanism of monomer transfer between two structurally distinct PrP oligomers

Date Published: July 26, 2017

Publisher: Public Library of Science

Author(s): Aurora Armiento, Philippe Moireau, Davy Martin, Nad’a Lepejova, Marie Doumic, Human Rezaei, Corinne Ida Lasmezas.


In mammals, Prion pathology refers to a class of infectious neuropathologies whose mechanism is based on the self-perpetuation of structural information stored in the pathological conformer. The characterisation of the PrP folding landscape has revealed the existence of a plethora of pathways conducing to the formation of structurally different assemblies with different biological properties. However, the biochemical interconnection between these diverse assemblies remains unclear. The PrP oligomerisation process leads to the formation of neurotoxic and soluble assemblies called O1 oligomers with a high size heterodispersity. By combining the measurements in time of size distribution and average size with kinetic models and data assimilation, we revealed the existence of at least two structurally distinct sets of assemblies, termed Oa and Ob, forming O1 assemblies. We propose a kinetic model representing the main processes in prion aggregation pathway: polymerisation, depolymerisation, and disintegration. The two groups interact by exchanging monomers through a disintegration process that increases the size of Oa. Our observations suggest that PrP oligomers constitute a highly dynamic population.

Partial Text

Transmissible spongiform encephalopathies (TSEs), or prion diseases, constitute a distinct group of fatal neurodegenerative diseases of humans and other animals. Creutzfeldt-Jakob disease (CJD), Gerstmann-Sträussler-Scheinker syndrome (GSS) and fatal familial insomnia (FFI) are the most common human prion diseases. The prion theory, which has been proposed to describe the self-perpetuation of structural information stored in prion assemblies, is now starting to be extended to a wider range of pathologies caused by protein misfolding and aggregation [1]. One of the intriguing aspects of the prion conversion process is the existence of broad panel of PrP assemblies that are highly heterogeneous in size [2]. The existence of such heterogeneity is associated to stochastic events and often to differences in the micro-environment where the conversion process occurs [3]. However, the diversity in the size of PrP assemblies could also be highly deterministic, as was observed with the oligomerisation process of recombinant PrP (recPrP) in a highly controlled environment [4]. The biochemical and biological implications of such a diversity remain unclear even if structurally different prion assemblies are claimed to be at the basis of the quasi-species phenomenon and prion adaptation to different hosts [5]. The existence of structurally different assemblies raises the question of their respective thermodynamic stability and the consequences of their coexistence in the same environment. Indeed, according to an Ostwald-like ripening phenomenon, the coexistence of assemblies structurally different could lead to a transfer phenomenon from the low stability to the high stability assemblies [6]. The ovine recPrP polymerisation at pH 4.1 and 7.2 leads to the formation of at least three structurally distinct neuro-toxic oligomers [7] whose size and ratio are each governed by the primary structure of PrP [8]. Indeed, at acidic pH the partial unfolding of ovine A136R154Q171 variant of PrP (ARQ) leads to the formation of three distinct oligomers, namely O1, O2 and O3. The biochemical characterisation of these oligomers strongly suggests that their respective folding pathways are different [4]. The O1 oligomers—which constitute the most thermodynamically stable between the three oligomer types—present a heterogeneity in size (Fig 1A).

Our step-by-step approach, from experimental analysis to data assimilation, leads us to a partly counter-intuitive conclusion: the existence of monomer exchange between two types of PrP oligomer assemblies. The formation of heterodisperse assemblies during the evolution of pathologies due to protein misassembly raises the question of their coexistence and their evolution. This phenomenon occurs during prion conversion for which several species could coexist and form what is also commonly called prion quasi-species [19, 20]. From a thermodynamical point of view, it is clear that not all assemblies are kinetically and energetically equivalent and some species with specific biological activities could be generated transitorily. However, the evolution of all these assemblies should follow specific thermodynamic and kinetic rules such as selection by higher stability and/or higher rate of formation. In the present work we demonstrate that there exist at least two types of oligomers which are simultaneously generated from monomeric PrP. In conditions that could biologically correspond to monomer depletion, we demonstrate that these two oligomer species are able to exchange monomers. The biological consequences of such a phenomenon could be the transitory apparition of physiopathological patterns and the existence of buffer assemblies serving as monomer reservoirs to enhance and maintain more stable assemblies. It is also clear that such a phenomenon should be considered for all therapeutic purposes.




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