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      PrP Expression, PrPSc Accumulation and Innervation of Splenic Compartments in Sheep Experimentally Infected with Scrapie

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          In prion disease, the peripheral expression of PrP C is necessary for the transfer of infectivity to the central nervous system. The spleen is involved in neuroinvasion and neural dissemination in prion diseases but the nature of this involvement is not known. The present study undertook the investigation of the spatial relationship between sites of PrP Sc accumulation, localisation of nerve fibres and PrP C expression in the tissue compartments of the spleen of scrapie-inoculated and control sheep.

          Methodology/Principal Findings

          Laser microdissection and quantitative PCR were used to determine PrP mRNA levels and results were compared with immunohistochemical protocols to distinguish PrP C and PrP Sc in tissue compartments of the spleen. In sheep experimentally infected with scrapie, the major sites of accumulation of PrP Sc in the spleen, namely the lymphoid nodules and the marginal zone, expressed low levels of PrP mRNA. Double immunohistochemical labelling for PrP Sc and the pan-nerve fibre marker, PGP, was used to evaluate the density of innervation of splenic tissue compartments and the intimacy of association between PrP Sc and nerves. Some nerve fibres were observed to accompany blood vessels into the PrP Sc-laden germinal centres. However, the close association between nerves and PrP Sc was most apparent in the marginal zone. Other sites of close association were adjacent to the wall of the central artery of PALS and the outer rim of germinal centres.


          The findings suggest that the degree of PrP Sc accumulation does not depend on the expression level of PrP C. Though several splenic compartments may contribute to neuroinvasion, the marginal zone may play a central role in being the compartment with most apparent association between nerves and PrP Sc.

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          Most cited references 33

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          Cells release prions in association with exosomes.

          Prion diseases are infectious neurodegenerative disorders linked to the accumulation in the central nervous system of the abnormally folded prion protein (PrP) scrapie (PrPsc), which is thought to be the infectious agent. Once present, PrPsc catalyzes the conversion of naturally occurring cellular PrP (PrPc) to PrPsc. Prion infection is usually initiated in peripheral organs, but the mechanisms involved in infectious spread to the brain are unclear. We found that both PrPc and PrPsc were actively released into the extracellular environment by PrP-expressing cells before and after infection with sheep prions, respectively. Based on Western blot with specific markers, MS, and morphological analysis, our data revealed that PrPc and PrPsc in the medium are associated with exosomes, membranous vesicles that are secreted upon fusion of multivesicular endosomes with the plasma membrane. Furthermore, we found that exosomes bearing PrPsc are infectious. Our data suggest that exosomes may contribute to intercellular membrane exchange and the spread of prions throughout the organism.
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            Prion protein (PrP) with amino-proximal deletions restoring susceptibility of PrP knockout mice to scrapie.

            The 'protein only' hypothesis postulates that the prion, the agent causing transmissible spongiform encephalopathies, is PrP(Sc), an isoform of the host protein PrP(C). Protease treatment of prion preparations cleaves off approximately 60 N-terminal residues of PrP(Sc) but does not abrogate infectivity. Disruption of the PrP gene in the mouse abolishes susceptibility to scrapie and prion replication. We have introduced into PrP knockout mice transgenes encoding wild-type PrP or PrP lacking 26 or 49 amino-proximal amino acids which are protease susceptible in PrP(Sc). Inoculation with prions led to fatal disease, prion propagation and accumulation of PrP(Sc) in mice expressing both wild-type and truncated PrPs. Within the framework of the 'protein only' hypothesis, this means that the amino-proximal segment of PrP(C) is not required either for its susceptibility to conversion into the pathogenic, infectious form of PrP or for the generation of PrP(Sc).
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              Prion protein biology.


                Author and article information

                Role: Editor
                PLoS One
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                3 September 2009
                : 4
                : 9
                [1 ]Department of Basic Sciences and Aquatic Medicine, Norwegian School of Veterinary Science, Oslo, Norway
                [2 ]Haematological Research Laboratory, Ullevål University Hospital, Oslo, Norway
                University of Liverpool, United Kingdom
                Author notes

                Conceived and designed the experiments: RS LA CMP GS TL AE. Performed the experiments: RS LA. Analyzed the data: RS LA. Contributed reagents/materials/analysis tools: CMP AE. Wrote the paper: RS. Review of manuscript and final approval: LA CMP GS TL AE.

                Sørby et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                Pages: 8
                Research Article
                Genetics and Genomics/Gene Expression
                Infectious Diseases/Prion Diseases



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