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Bach C. We do not know whether authentic K will emerge upon further serial transmission of K MH. Surprisingly, K propagated first in RNA-depleted mouse substrate and then normal hamster substrate designated as K M H resulted in a new disease phenotype. This disease phenotype was characterized by a longer incubation time and clinical duration of disease relative to the original K or K MH group and altered neuropathological features.
We do not know whether the incubation time of K M H will shorten upon further serial transmission. In summary, three different outcomes of prion transmission were observed in animals depending on the presence or absence of RNA in PMCAb reactions.
Therefore, the lack of clinical disease in the first passage cannot be attributed to the differences in the amino acid sequences of the PMCAb-derived inocula and PrP C of the host. Instead, the lack of the disease could be in part due to a decline of prion-specific infectivity during serial PMCAb.
Indeed, previous studies reported that the specific prion infectivity of K declines gradually during serial PMCA [ 37 ]. Nevertheless, it is difficult to attribute three asymptomatic serial passages of K MH solely to a low specific infectivity of the PMCAb-derived products. In fact, in the 2 nd passage most of the animals of MH and K M H groups showed considerable increase in the intensity of PrP Sc signal relative to the signal intensity of the corresponding inocula, whereas the signal intensity for most of the animals of K MH group was the same as in corresponding inoculum Fig 2B.
This could be due to intrinsically slow replication rate of K MH , its fast clearance, or both. Consistent with this conclusion, brain-derived K MH was found to be considerably less resistant to proteolytic digestion at high concentrations of PK in comparison to the brain-derived MH or K M H. The hamster-adapted prion strain K used in the current study originated from the natural pool of scrapie that was isolated from the Cheviot breed in [ 38 ]. Considering this history of interspecies passages, it is not surprising that K possesses certain level of plasticity and is able of overcoming a hamster-to-mouse species barrier.
While K was initially regarded as nonpathogenic for mice as it failed to produce clinical disease in the first passage [ 40 ], subsequent studies documented slow or silent replication of K in mice that could lead to a clinical disease upon serial transmission [ 41 — 43 ]. Moreover, transgenic mice that overexpress mouse PrP C Tg20 developed clinical diseases in the first passage upon transmission of Sc, the hamster-adapted strain of the same origin as K [ 34 ].
Notably, the prion diseases observed in mice upon inoculation of PMCA-derived PrP Sc seeded with K and amplified in mouse substrate showed unique disease phenotype [ 33 ].
Remarkably, other studies demonstrated that mice infected directly with hamster Sc PrP Sc or PrP Sc obtained upon replication of Sc in PMCA with mouse substrate produced different disease phenotypes upon serial transmission [ 34 ]. Those studies suggested that prion replication environment, whether it is in vitro environment of PMCA or environment of cellular sites of prion replication in a brain, is an important factor that determines disease phenotype upon cross-species transmission.
What is the role of RNA in prion replication? In previous studies, cellular and synthetic RNAs were shown to stimulate replication of prions in vitro [ 4 , 21 ]. The degree of the stimulating effect was found to be species- and strain-dependent [ 25 , 30 , 31 ]. While RNAs strongly facilitated replication of all hamster strains examined, the effect on replication of mouse strains was considerably less pronounced and strain-dependent [ 25 , 30 , 31 ].
Considering that the hamster strains are predominantly di-glycosylated, whereas the glycosylation statuses of mouse strains are variable, one can speculate that the species- and strain-dependency of the RNA effect could be due to differences in pattern or density of carbohydrate epitopes on PrP Sc surface [ 44 ]. It is not clear whether RNAs assist prion replication in vivo. On one hand, convincing evidence have been presented that prion-specific polynucleotides are lacking in PrP Sc particles isolated from Scinfected animals, the hamster-adapted strain of the same origin as K [ 45 ].
On the other hand, RNA molecules were found to co-localize with large extracellular PrP Sc aggregates in hamsters infected with Sc [ 29 ]. Moreover, synthetic homopolymeric polynucleotides of sizes above bases were found to stimulate conversion in vitro and form nuclease-resistant complexes with PrP molecules during PMCA reactions [ 29 , 46 ]. The detailed molecular mechanism behind the effects of RNA on prion replication is not known.
Yet, it is reasonable to conclude that at least in vitro RNA provides favorable biochemical environment for prion replication. As suggested by previous studies, it is highly unlikely that the stimulating effects could be attributed to specific RNA sequences [ 4 , 46 ]. Instead, it appears that the polyanionic nature of RNA and, perhaps, its unique conformational features are important.
Application of PMCAb for examining the contribution of biochemical environment on fate of prion stain adaptation could be regarded as a main limitation of the current work. At the same time, the experimental design that involves PMCAb provides an opportunity for probing the hypothesis, which otherwise would be difficult, if not impossible, to test.
Based on the results presented in the current work, one can speculate that accessibility of the cellular sites of prion replication to RNAs could be one of the factors that contribute to determining the fate of prion strain adaptation upon cross-species transmission. Among other factors that control the outcomes of the cross-species transmission are the transmission route and involvement of secondary lymphoid tissues in prion replication [ 47 ].
While it is difficult to fully disentangle strain adaptation in vivo from the adaptation that occurs during PMCAb reactions, the results of our previous studies helped to assess the contribution of the PMCAb technique itself to the apparent strain adaptation [ 48 ].
In those experiments, 10 3 -fold diluted K brain material was subjected to 24 serial PMCAb rounds with dilution between rounds using only hamster NBH as a substrate. This experiment is consistent with the previous data that amplification of K in PMCAb in hamster substrate reduces specific prion infectivity, yet does not alter the disease phenotype [ 37 ].
Nevertheless, the fact that three serial passages were required for K MH to exhibit the disease phenotype similar to K suggests that additional strain adaptation was taking place in hamsters during serial transmission.
The results of the current study can be discussed within two broad hypotheses—the cloud and deformed templating hypotheses, which are not mutually exclusive. According to the cloud hypothesis, the populations of PrP Sc particles are intrinsically heterogeneous within individual strains or isolates due to spontaneous conformational mutations. PrP Sc populations might consist of a major and a number of minor structural variants [ 49 , 50 ].
Upon a cross-species transmission, a minor PrP Sc variant might become predominant in a new host due to changes in selection criteria and give rise to a new disease phenotype. If the cloud hypothesis accounts for the changes in fate of prion adaptation observed in the current studies, the current results suggest that altering a biochemical environment of prions replication in vitro gives a selective advantage to one of preexisting minor PrP Sc variants resulting in an altered disease phenotype.
The deformed templating model postulates that a change in replication environment plays an active role in generating new PrP Sc variants, in addition to its role in imposing a new selective pressure [ 51 , 52 ]. PrP Sc templates that do not fit well to a new environment still can seed altered PrP Sc structural variants via deformed templating. While the majority of the newly generated variants might not replicate efficiently in altered environment, a variant that fits well to the new environment will eventually emerge through multiple trial-and-error seeding events.
It would be challenging to document what mechanism takes place, as it requires experimental testing of whether a minor PrP Sc variant associated with a new disease phenotype pre-existed in the original prion isolate or strain.
Moreover, deformed templating mechanism describes well the evolution of prion strains of synthetic origin that were induced by recombinant PrP fibrils in animals despite fundamental structural differences between recombinant PrP fibrils and authentic PrP Sc [ 53 — 56 ]. Regardless of which hypothesis is correct, the current work highlights a new important role of cofactor environment in prion cross-species transmission and adaptation. How changes in replication environment, and specifically RNA-depletion, can affect the fate of a prion strain?
Previously, we suggested that adequate replication environment is necessary for insuring high fidelity of prion strain replication [ 32 ]. If this is true, RNA depletion during propagation of RNA-dependent strains could be compensated in part by other cellular polyanions creating heterogeneous replication environments and boosting diversity of the PrP Sc variants. The current results support this mechanism, which is speculative at present time. Notably, in previous studies three mouse strains maintained their highly infectious and pathogenic state upon replication in PMCA in the presence of a lipid phosphatidylethanolamine as a sole cofactor, yet lost their original strain-specific features and converged into a single new strain [ 23 ].
In a second passage, the clinical signs of the disease reversed to the original RML-specific signs suggesting that the original RML variant overcompeted the new variant that emerged under the RNA-depleted conditions [ 31 ]. In summary, the current and previous studies suggest that maintaining adequate replication environment might be essential for maintaining prion strainness.
Recent study generated several novel prion strains by propagating chronic wasting disease prion isolates in PMCA that utilized recombinant bank vole PrP as a substrate and PrP knock-out mouse brain homogenate as a source of cofactors, and then replacing mouse brain homogenate with different cofactors of polyanionic nature [ 57 ]. Remarkably, the same set of PrP Sc structures were generated in non-seeded or spontaneous PMCA reactions conducted only in the presence of recombinant bank vole PrP substrate and polyanionic cofactors [ 57 ].
These data suggest that cofactors might confine spontaneous PrP misfolding pathways in vitro while guiding it toward limited set of PrP Sc structures that give rise to new prion strains upon transmission in animals.
The current study tested the effect of RNA during cross-species adaptation and suggests that RNAs might be important for ensuring a high fidelity of prion replication. In addition to cellular cofactors, what other parameters might be involved in determining the fate of prion cross-species transmission and strain adaptation? N-linked glycans represent the source of enormous diversity with respect to their composition and structure, yet their role in prion pathogenesis remains largely unknown.
Our recent work revealed that PrP C sialoglycoforms are recruited into PrP Sc selectively in a strain-specific manner [ 58 ]. Based on 2D analysis of glycosylation of individual strains, we proposed that individual strain-specific structures of PrP Sc govern selection of PrP C sialoglycoforms that can be accommodated within individual structures producing a strain-specific pattern of carbohydrate epitopes on PrP Sc surface [ 44 , 59 ].
In addition to a strain-specific structure, the pattern of carbohydrate epitopes is likely to be shaped by a host due to species-specific differences in the spectrum of N-linked glycans synthetized by different hosts. On one hand, transmission to a new host is likely to change carbohydrate patterns due to changes in PrP Sc structure and exposure to a new pool of N-linked glycans in a new host.
On the other hand, new pool of N-linked glycans might also play a role in selection of minor structural PrP Sc variants in a new host.
An interplay between the effect of PrP Sc structure on selection of sialoglycoforms and conversely the effect of an altered pool of N-linked glycans on selection of PrP Sc structural variants might explain the fact that stabilization of a new strain phenotype sometimes requires multiple serial passaging. Nevertheless, the role of N-linked glycans in determining the fate of prion strain adaptation has yet to be explored. This study was carried out in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health.
Animals from the first passage did not develop any clinical symptoms and were euthanized at days post inoculation by asphyxiation with CO 2 Table 1. Animals that developed clinical signs were sacrificed at the terminal stages of the diseases as indicated in Table 1 , whereas animals that did not develop clinical signs were sacrificed at days or days post inoculation for the second and third passages, respectively Table 1. PMCAb procedure has been described in detail elsewhere [ 60 ].
Briefly, healthy hamsters or mice were euthanized and immediately perfused with PBS, pH 7. The brains were ground at low speed until homogeneous, and then five additional strokes completed the homogenization. Samples in 0. The digestion was terminated by addition of SDS-sample buffer and boiling for 10 min. The samples were centrifuged 5 min at 16, g to remove debris. The digestion was terminated by addition of SDS-sample buffer and heating for 10 min in a boiling water bath.
Analysis of GdnHCl-induced denaturation was performed as previously described [ 54 ]. Target bands were selected using a uniform rectangular sampling area that encompassed the band of interest. Background optical density of an equal area from the same blot was determined and subsequently subtracted from the density of the bands.
Three independent brains were analyzed for each sample type, for calculating mean and standard deviations. The plots were drawn in Microsoft Excel. Histopathological studies were performed on three animals per group. Formalin fixed brain halves were divided at the midline. As age-matched normal controls for the histopathology study, Golden Syrian hamsters of days old were used.
This age corresponds to the biological age of the oldest experimental group euthanized in the current work. DNA markers were used as running standards. Representative images of the frontal cortex, hippocampus, thalamus, caudate-putamen, or cerebellum stained with hematoxylin and eosin. The lesion profile was obtained by averaging the scores for spongiform change, neuronal loss and gliosis for three animals within each group.
The PrP immunopositivity profile was obtained by averaging the scores for three animals within each group. Prions also cause disease in a wide variety of other animals, including scrapie in sheep and bovine spongiform encephalopathy BSE in cows.
Collectively these diseases are known as transmissible spongiform encephalopathies. Transmission of the disease occurred during a ritual funeral process in which the brain of a dead tribe member was removed from the skull, cooked and eaten.
Scientific analysis of the brains of people who had died from CJD or kuru showed that their brain tissue had a spongiform appearance, that is, there were holes where cells ought to be, indicating an encephalopathy, or reduction in the number of brain cells. Carleton Gajdusek, working at the U. National Institutes of Health, demonstrated that extracts of brain prepared from people who had died of CJD or kuru could cause a similar disease when inoculated into the brain of chimpanzees.
These experiments obviously suggested the presence of an infectious agent. That inference has been confirmed by the inadvertent transmission of CJD to patients undergoing various medical treatments, such as corneal transplants and human growth hormone therapy. The pattern of inheritance was recognized as being autosomal and dominant, meaning that if a parent developed GSS, there was a 50 percent chance that a child of either sex would also develop the disease.
Any explanation for the cause of a prion disease therefore has to account for random, inherited and transmitted variants of the disease. We now know that a normal cellular protein, called PrP for proteinaceous infectious particle and which is found in all of us, is centrally involved in the spread of prion diseases. This protein consists of about amino acids. This is called the virino hypothesis. Viruses consist of proteins and nucleic acids that are specified by the virus genome.
A virino would also consist of proteins and nucleic acids, but the protein component is specified by the host genome, not the pathogen genome. In support of the virino hypothesis is the existence of different strains of prions that cause differing patterns of disease and breed true; the existence of strains in pathogens is usually the result of changes in the nucleic acid sequence of the infectious agent.
Scientists have not found any nucleic acid associated with a prion, however, despite intensive efforts in many laboratories. Furthermore, prions appear to remain infectious even after being exposed to treatments that destroy nucleic acids.
The theory holds that PrP is normally in a stable shape pN that does not cause disease. The protein can be flipped, however, into an abnormal shape pD that does cause disease.
Exponential amplification of the prion converting pN into pD in the body would then result in disease. Occasional, sporadic cases of prion diseases arise in middle or old age, presumably because there is a very small but real chance that pN can spontaneously flip to pD; the cumulative likelihood of such a flip grows over the years. This change would increase the probability of pN transforming into pD, so that the disease would almost certainly occur.
Recently the structure of the core part of the PrP protein was determined by magnetic resonance image analysis.
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