Stabilization of a Prion Strain of Synthetic Origin Requires Multiple Serial Passages

Abstract

Background: Strain adaptation accompanies cross-species transmission of prions. Results: Adaptation of a strain of synthetic origin was observed within the same host species. Conclusion: When induced by recombinant PrP fibrils, PrPSc properties evolve over multiple serial passages within the same host. Significance: The phenomenon of prion strain adaptation is more common than generally thought.

Truncated forms of the prion protein PrP demonstrate the need for complexity in prion structure

“…This route of infection represents a pathway parallel to the natural etiology and would most likely be caused by a process of deformed templating (heterogeneous seeding). 17,18,19 Regardless of the mechanism of infectivity, it is clear that the generic stacked-sheet structure has very little infectivity if any, and is very different, both structurally and functionally, from the b-solenoidal structure. HET-s exhibits a similar polymorphism: 20 the wild-type protein at neutral pH and many mutants form b-solenoids, but other mutants and the wildtype protein at acidic pH form non-infectious 21 stacked sheets.…”

“…This is the process of deformed templating, and has been demonstrated in HET-s 19,28 and PrP. 17 Amyloids with distinct architectures can interact with one another, without requiring in vivo cofactors. Deformed templating provides a mechanism for a preferred prion structure to be reached from different initial nucleating agents, although the process may require several passages through animals.…”

“…Deformed templating provides a mechanism for a preferred prion structure to be reached from different initial nucleating agents, although the process may require several passages through animals. 17,30 In summary, small fragments of prion proteins have at best limited value as structural models, but infectious fragments, which have at least until now only included fragments of considerable size such as PrP55, may well have value in heterogeneous seeding or deformed templating studies of prion strains, strain adaptation, and interspecies prion transmission.…”

“…27 Perhaps the greatest value for prion studies of at least the larger fragments of PrP lies in their use not as structural models for the active prion itself, but as templates that illustrate the phenomenon of heterogeneous seeding or deformed templating. 17,18,19,28 The infectivity of PrP55, for example, may well come from heterogeneous seeding, that is, seeding between distinct amyloid architectures. With two rungs of a b-solenoid, PrP55 could easily contain a structured segment that can act as a seed, in distinct contrast to PrP21 and other short, noninfectious fragments.…”

Heterogeneous seeding of HET-s(218–289) and the mutability of prion structures

“…During serial passaging, recPrP undergoes adaptation to the new host conditions and acquires the biophysical features of PrP Sc , 24,26,27 parallel to the reproduction of homogeneous seeding kinetics following serial passage of heterogeneously seeded HET-s(218-289) fibrils. The similarities between these results suggest that strain adaptation by way of changing molecular structure is a common biophysical feature of prions.…”