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Changes in prion replication environment cause prion strain mutation.

ABSTRACT: Interspecies prion transmission often leads to stable changes in physical and biological features of prion strains, a phenomenon referred to as a strain mutation. It remains unknown whether changes in the replication environment in the absence of changes in PrP primary structure can be a source of strain mutations. To approach this question, RNA content was altered in the course of amplification of hamster strains in serial protein misfolding cyclic amplification (sPMCAb). On adaptation to an RNA-depleted environment and then readaptation to an environment containing RNA, strain 263K gave rise to a novel PrP(Sc) conformation referred to as 263K(R+), which is characterized by very low conformational stability, high sensitivity to proteolytic digestion, and a replication rate of 10(6)-fold/PMCAb round, which exceeded that of 263K by almost 10(4)-fold. A series of PMCAb experiments revealed that 263K(R+) was lacking in brain-derived 263K material, but emerged de novo as a result of changes in RNA content. A similar transformation was also observed for strain Hyper, suggesting that this phenomenon was not limited to 263K. The current work demonstrates that dramatic PrP(Sc) transformations can be induced by changes in the prion replication environment and without changes in PrP primary structure.

SUBMITTER: Gonzalez-Montalban N

PROVIDER: S-EPMC3752540 | biostudies-literature | 2013 Sep

REPOSITORIES: biostudies-literature

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Changes in prion replication environment cause prion strain mutation.

Gonzalez-Montalban Nuria N Lee Young Jin YJ Makarava Natallia N Savtchenko Regina R Baskakov Ilia V IV

FASEB journal : official publication of the Federation of American Societies for Experimental Biology 20130531 9

Interspecies prion transmission often leads to stable changes in physical and biological features of prion strains, a phenomenon referred to as a strain mutation. It remains unknown whether changes in the replication environment in the absence of changes in PrP primary structure can be a source of strain mutations. To approach this question, RNA content was altered in the course of amplification of hamster strains in serial protein misfolding cyclic amplification (sPMCAb). On adaptation to an RN ...[more]

PMID: 23729586

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Project description:Prions are proteinaceous infectious agents responsible for fatal neurodegenerative diseases in animals and humans. They are essentially composed of PrP(Sc), an aggregated, misfolded conformer of the ubiquitously expressed host-encoded prion protein (PrP(C)). Stable variations in PrP(Sc) conformation are assumed to encode the phenotypically tangible prion strains diversity. However the direct contribution of PrP(Sc) quaternary structure to the strain biological information remains mostly unknown. Applying a sedimentation velocity fractionation technique to a panel of ovine prion strains, classified as fast and slow according to their incubation time in ovine PrP transgenic mice, has previously led to the observation that the relationship between prion infectivity and PrP(Sc) quaternary structure was not univocal. For the fast strains specifically, infectivity sedimented slowly and segregated from the bulk of proteinase-K resistant PrP(Sc). To carefully separate the respective contributions of size and density to this hydrodynamic behavior, we performed sedimentation at the equilibrium and varied the solubilization conditions. The density profile of prion infectivity and proteinase-K resistant PrP(Sc) tended to overlap whatever the strain, fast or slow, leaving only size as the main responsible factor for the specific velocity properties of the fast strain most infectious component. We further show that this velocity-isolable population of discrete assemblies perfectly resists limited proteolysis and that its templating activity, as assessed by protein misfolding cyclic amplification outcompetes by several orders of magnitude that of the bulk of larger size PrP(Sc) aggregates. Together, the tight correlation between small size, conversion efficiency and duration of disease establishes PrP(Sc) quaternary structure as a determining factor of prion replication dynamics. For certain strains, a subset of PrP assemblies appears to be the best template for prion replication. This has important implications for fundamental studies on prions.

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Changes in prion replication environment cause prion strain mutation.

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Changes in prion replication environment cause prion strain mutation.

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