Structural features distinguishing infectious ex vivo mammalian prions from non-infectious fibrillar assemblies generated in vitro
Seeded polymerisation of proteins forming amyloid fibres and their spread in tissues has been implicated in the pathogenesis of multiple neurodegenerative diseases: so called "prion-like" mechanisms. While ex vivo mammalian prions, composed of multichain assemblies of misfolded host-encode...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Group Publishing
2019
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| Online Access: | https://repository.londonmet.ac.uk/4564/1/s41598-018-36700-w.pdf |
| _version_ | 1804072336867983360 |
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| author | Terry, Cassandra Harniman, Robert L. Sells, Jessica Wenborn, Adam Joiner, Susan Saibil, Helen R. Miles, Mervyn J. Collinge, John Wadsworth, Jonathan D. F. |
| author_facet | Terry, Cassandra Harniman, Robert L. Sells, Jessica Wenborn, Adam Joiner, Susan Saibil, Helen R. Miles, Mervyn J. Collinge, John Wadsworth, Jonathan D. F. |
| author_sort | Terry, Cassandra |
| collection | LMU |
| description | Seeded polymerisation of proteins forming amyloid fibres and their spread in tissues has been implicated in the pathogenesis of multiple neurodegenerative diseases: so called "prion-like" mechanisms. While ex vivo mammalian prions, composed of multichain assemblies of misfolded host-encoded prion protein (PrP), act as lethal infectious agents, PrP amyloid fibrils produced in vitro generally do not. The high-resolution structure of authentic infectious prions and the structural basis of prion strain diversity remain unknown. Here we use cryo-electron microscopy and atomic force microscopy to examine the structure of highly infectious PrP rods isolated from mouse brain in comparison to non-infectious recombinant PrP fibrils generated in vitro. Non-infectious recombinant PrP fibrils are 10 nm wide single fibres, with a double helical repeating substructure displaying small variations in adhesive force interactions across their width. In contrast, infectious PrP rods are 20 nm wide and contain two fibres, each with a double helical repeating substructure, separated by a central gap of 8-10 nm in width. This gap contains an irregularly structured material whose adhesive force properties are strikingly different to that of the fibres, suggestive of a distinct composition. The structure of the infectious PrP rods, which cause lethal neurodegeneration, readily differentiates them from all other protein assemblies so far characterised in other neurodegenerative diseases. |
| first_indexed | 2024-07-09T03:57:32Z |
| format | Article |
| id | oai:repository.londonmet.ac.uk:4564 |
| institution | London Metropolitan University |
| language | English |
| last_indexed | 2024-07-09T03:57:32Z |
| publishDate | 2019 |
| publisher | Nature Group Publishing |
| record_format | eprints |
| spelling | oai:repository.londonmet.ac.uk:45642020-04-21T13:06:01Z http://repository.londonmet.ac.uk/4564/ Structural features distinguishing infectious ex vivo mammalian prions from non-infectious fibrillar assemblies generated in vitro Terry, Cassandra Harniman, Robert L. Sells, Jessica Wenborn, Adam Joiner, Susan Saibil, Helen R. Miles, Mervyn J. Collinge, John Wadsworth, Jonathan D. F. 570 Life sciences; biology Seeded polymerisation of proteins forming amyloid fibres and their spread in tissues has been implicated in the pathogenesis of multiple neurodegenerative diseases: so called "prion-like" mechanisms. While ex vivo mammalian prions, composed of multichain assemblies of misfolded host-encoded prion protein (PrP), act as lethal infectious agents, PrP amyloid fibrils produced in vitro generally do not. The high-resolution structure of authentic infectious prions and the structural basis of prion strain diversity remain unknown. Here we use cryo-electron microscopy and atomic force microscopy to examine the structure of highly infectious PrP rods isolated from mouse brain in comparison to non-infectious recombinant PrP fibrils generated in vitro. Non-infectious recombinant PrP fibrils are 10 nm wide single fibres, with a double helical repeating substructure displaying small variations in adhesive force interactions across their width. In contrast, infectious PrP rods are 20 nm wide and contain two fibres, each with a double helical repeating substructure, separated by a central gap of 8-10 nm in width. This gap contains an irregularly structured material whose adhesive force properties are strikingly different to that of the fibres, suggestive of a distinct composition. The structure of the infectious PrP rods, which cause lethal neurodegeneration, readily differentiates them from all other protein assemblies so far characterised in other neurodegenerative diseases. Nature Group Publishing 2019-01-23 Article PeerReviewed text en https://repository.londonmet.ac.uk/4564/1/s41598-018-36700-w.pdf Terry, Cassandra, Harniman, Robert L., Sells, Jessica, Wenborn, Adam, Joiner, Susan, Saibil, Helen R., Miles, Mervyn J., Collinge, John and Wadsworth, Jonathan D. F. (2019) Structural features distinguishing infectious ex vivo mammalian prions from non-infectious fibrillar assemblies generated in vitro. Scientific Reports, 9 (376). ISSN 2045-2322 https://www.nature.com/srep/ 10.1038/s41598-018-36700-w |
| spellingShingle | 570 Life sciences; biology Terry, Cassandra Harniman, Robert L. Sells, Jessica Wenborn, Adam Joiner, Susan Saibil, Helen R. Miles, Mervyn J. Collinge, John Wadsworth, Jonathan D. F. Structural features distinguishing infectious ex vivo mammalian prions from non-infectious fibrillar assemblies generated in vitro |
| title | Structural features distinguishing infectious ex vivo mammalian prions from non-infectious fibrillar assemblies generated in vitro |
| title_full | Structural features distinguishing infectious ex vivo mammalian prions from non-infectious fibrillar assemblies generated in vitro |
| title_fullStr | Structural features distinguishing infectious ex vivo mammalian prions from non-infectious fibrillar assemblies generated in vitro |
| title_full_unstemmed | Structural features distinguishing infectious ex vivo mammalian prions from non-infectious fibrillar assemblies generated in vitro |
| title_short | Structural features distinguishing infectious ex vivo mammalian prions from non-infectious fibrillar assemblies generated in vitro |
| title_sort | structural features distinguishing infectious ex vivo mammalian prions from non infectious fibrillar assemblies generated in vitro |
| topic | 570 Life sciences; biology |
| url | https://repository.londonmet.ac.uk/4564/1/s41598-018-36700-w.pdf |
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