Preserving prion strain identity upon replication of prions in vitro using recombinant prion protein
Abstract Last decade witnessed an enormous progress in generating authentic infectious prions or PrPSc in vitro using recombinant prion protein (rPrP). Previous work established that rPrP that lacks posttranslational modification is able to support replication of highly infectious PrPSc with assista...
| Main Authors: | , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2018-09-01
|
| Series: | Acta Neuropathologica Communications |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s40478-018-0597-y |
| _version_ | 1824042147086598144 |
|---|---|
| author | Natallia Makarava Regina Savtchenko Peter Lasch Michael Beekes Ilia V. Baskakov |
| author_facet | Natallia Makarava Regina Savtchenko Peter Lasch Michael Beekes Ilia V. Baskakov |
| author_sort | Natallia Makarava |
| collection | DOAJ |
| description | Abstract Last decade witnessed an enormous progress in generating authentic infectious prions or PrPSc in vitro using recombinant prion protein (rPrP). Previous work established that rPrP that lacks posttranslational modification is able to support replication of highly infectious PrPSc with assistance of cofactors of polyanionic nature and/or lipids. Unexpectedly, previous studies also revealed that seeding of rPrP by brain-derived PrPSc gave rise to new prion strains with new disease phenotypes documenting loss of a strain identity upon replication in rPrP substrate. Up to now, it remains unclear whether prion strain identity can be preserved upon replication in rPrP. The current study reports that faithful replication of hamster strain SSLOW could be achieved in vitro using rPrP as a substrate. We found that a mixture of phosphatidylethanolamine (PE) and synthetic nucleic acid polyA was sufficient for stable replication of hamster brain-derived SSLOW PrPSc in serial Protein Misfolding Cyclic Amplification (sPMCA) that uses hamster rPrP as a substrate. The disease phenotype generated in hamsters upon transmission of recombinant PrPSc produced in vitro was strikingly similar to the original SSLOW diseases phenotype with respect to the incubation time to disease, as well as clinical, neuropathological and biochemical features. Infrared microspectroscopy (IR-MSP) indicated that PrPSc produced in animals upon transmission of recombinant PrPSc is structurally similar if not identical to the original SSLOW PrPSc. The current study is the first to demonstrate that rPrP can support replication of brain-derived PrPSc while preserving its strain identity. In addition, the current work is the first to document that successful propagation of a hamster strain could be achieved in vitro using hamster rPrP. |
| first_indexed | 2024-12-22T23:37:09Z |
| format | Article |
| id | doaj.art-9f8d973d32fc44b3adf47260e4a51a43 |
| institution | Directory Open Access Journal |
| issn | 2051-5960 |
| language | English |
| last_indexed | 2024-12-22T23:37:09Z |
| publishDate | 2018-09-01 |
| publisher | BMC |
| record_format | Article |
| series | Acta Neuropathologica Communications |
| spelling | doaj.art-9f8d973d32fc44b3adf47260e4a51a432022-12-21T18:08:33ZengBMCActa Neuropathologica Communications2051-59602018-09-016111410.1186/s40478-018-0597-yPreserving prion strain identity upon replication of prions in vitro using recombinant prion proteinNatallia Makarava0Regina Savtchenko1Peter Lasch2Michael Beekes3Ilia V. Baskakov4Center for Biomedical Engineering and Technology, University of Maryland School of MedicineCenter for Biomedical Engineering and Technology, University of Maryland School of MedicineCentre for Biological Threats and Special Pathogens, Robert Koch-InstituteCentre for Biological Threats and Special Pathogens, Robert Koch-InstituteCenter for Biomedical Engineering and Technology, University of Maryland School of MedicineAbstract Last decade witnessed an enormous progress in generating authentic infectious prions or PrPSc in vitro using recombinant prion protein (rPrP). Previous work established that rPrP that lacks posttranslational modification is able to support replication of highly infectious PrPSc with assistance of cofactors of polyanionic nature and/or lipids. Unexpectedly, previous studies also revealed that seeding of rPrP by brain-derived PrPSc gave rise to new prion strains with new disease phenotypes documenting loss of a strain identity upon replication in rPrP substrate. Up to now, it remains unclear whether prion strain identity can be preserved upon replication in rPrP. The current study reports that faithful replication of hamster strain SSLOW could be achieved in vitro using rPrP as a substrate. We found that a mixture of phosphatidylethanolamine (PE) and synthetic nucleic acid polyA was sufficient for stable replication of hamster brain-derived SSLOW PrPSc in serial Protein Misfolding Cyclic Amplification (sPMCA) that uses hamster rPrP as a substrate. The disease phenotype generated in hamsters upon transmission of recombinant PrPSc produced in vitro was strikingly similar to the original SSLOW diseases phenotype with respect to the incubation time to disease, as well as clinical, neuropathological and biochemical features. Infrared microspectroscopy (IR-MSP) indicated that PrPSc produced in animals upon transmission of recombinant PrPSc is structurally similar if not identical to the original SSLOW PrPSc. The current study is the first to demonstrate that rPrP can support replication of brain-derived PrPSc while preserving its strain identity. In addition, the current work is the first to document that successful propagation of a hamster strain could be achieved in vitro using hamster rPrP.http://link.springer.com/article/10.1186/s40478-018-0597-yPrionsPrion diseasesPrion strainReplication cofactorsRecombinant prion protein |
| spellingShingle | Natallia Makarava Regina Savtchenko Peter Lasch Michael Beekes Ilia V. Baskakov Preserving prion strain identity upon replication of prions in vitro using recombinant prion protein Acta Neuropathologica Communications Prions Prion diseases Prion strain Replication cofactors Recombinant prion protein |
| title | Preserving prion strain identity upon replication of prions in vitro using recombinant prion protein |
| title_full | Preserving prion strain identity upon replication of prions in vitro using recombinant prion protein |
| title_fullStr | Preserving prion strain identity upon replication of prions in vitro using recombinant prion protein |
| title_full_unstemmed | Preserving prion strain identity upon replication of prions in vitro using recombinant prion protein |
| title_short | Preserving prion strain identity upon replication of prions in vitro using recombinant prion protein |
| title_sort | preserving prion strain identity upon replication of prions in vitro using recombinant prion protein |
| topic | Prions Prion diseases Prion strain Replication cofactors Recombinant prion protein |
| url | http://link.springer.com/article/10.1186/s40478-018-0597-y |
| work_keys_str_mv | AT natalliamakarava preservingprionstrainidentityuponreplicationofprionsinvitrousingrecombinantprionprotein AT reginasavtchenko preservingprionstrainidentityuponreplicationofprionsinvitrousingrecombinantprionprotein AT peterlasch preservingprionstrainidentityuponreplicationofprionsinvitrousingrecombinantprionprotein AT michaelbeekes preservingprionstrainidentityuponreplicationofprionsinvitrousingrecombinantprionprotein AT iliavbaskakov preservingprionstrainidentityuponreplicationofprionsinvitrousingrecombinantprionprotein |