title: Ex vivo mammalian prions are formed of paired double helical prion protein fibrils.
abstract: Mammalian prions are hypothesized to be fibrillar or amyloid forms of prion protein (PrP), but structures observed to date have not been definitively correlated with infectivity and the three-dimensional structure of infectious prions has remained obscure. Recently, we developed novel methods to obtain exceptionally pure preparations of prions from mouse brain and showed that pathogenic PrP in these high-titre preparations is assembled into rod-like assemblies. Here, we have used precise cell culture-based prion infectivity assays to define the physical relationship between the PrP rods and prion infectivity and have used electron tomography to define their architecture. We show that infectious PrP rods isolated from multiple prion strains have a common hierarchical assembly comprising twisted pairs of short fibres with repeating substructure. The architecture of the PrP rods provides a new structural basis for understanding prion infectivity and can explain the inability to systematically generate high-titre synthetic prions from recombinant PrP.
authors.affiliation: MRC Prion Unit and Department of Neurodegenerative Disease, UCL Institute of Neurology, National Hospital for Neurology and Neurosurgery, Queen Square, London WC1N 3BG, UK.
authors.forename: Cassandra
authors.initials: C
authors.lastname: Terry
authors.affiliation: MRC Prion Unit and Department of Neurodegenerative Disease, UCL Institute of Neurology, National Hospital for Neurology and Neurosurgery, Queen Square, London WC1N 3BG, UK.
authors.forename: Adam
authors.initials: A
authors.lastname: Wenborn
authors.affiliation: MRC Prion Unit and Department of Neurodegenerative Disease, UCL Institute of Neurology, National Hospital for Neurology and Neurosurgery, Queen Square, London WC1N 3BG, UK.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Gros
authors.affiliation: MRC Prion Unit and Department of Neurodegenerative Disease, UCL Institute of Neurology, National Hospital for Neurology and Neurosurgery, Queen Square, London WC1N 3BG, UK.
authors.forename: Jessica
authors.initials: J
authors.lastname: Sells
authors.affiliation: MRC Prion Unit and Department of Neurodegenerative Disease, UCL Institute of Neurology, National Hospital for Neurology and Neurosurgery, Queen Square, London WC1N 3BG, UK.
authors.forename: Susan
authors.initials: S
authors.lastname: Joiner
authors.affiliation: MRC Prion Unit and Department of Neurodegenerative Disease, UCL Institute of Neurology, National Hospital for Neurology and Neurosurgery, Queen Square, London WC1N 3BG, UK.
authors.forename: Laszlo L P
authors.initials: LL
authors.lastname: Hosszu
authors.affiliation: MRC Prion Unit and Department of Neurodegenerative Disease, UCL Institute of Neurology, National Hospital for Neurology and Neurosurgery, Queen Square, London WC1N 3BG, UK.
authors.forename: M Howard
authors.initials: MH
authors.lastname: Tattum
authors.affiliation: Institute of Structural and Molecular Biology, Department of Biological Sciences, Birkbeck College, University of London, Malet Street, London WC1E 7HX, UK.
authors.forename: Silvia
authors.initials: S
authors.lastname: Panico
authors.affiliation: Institute of Structural and Molecular Biology, Department of Biological Sciences, Birkbeck College, University of London, Malet Street, London WC1E 7HX, UK.
authors.forename: Daniel K
authors.initials: DK
authors.lastname: Clare
authors.affiliation: MRC Prion Unit and Department of Neurodegenerative Disease, UCL Institute of Neurology, National Hospital for Neurology and Neurosurgery, Queen Square, London WC1N 3BG, UK j.collinge@prion.ucl.ac.uk.
authors.forename: John
authors.initials: J
authors.lastname: Collinge
authors.affiliation: Institute of Structural and Molecular Biology, Department of Biological Sciences, Birkbeck College, University of London, Malet Street, London WC1E 7HX, UK h.saibil@mail.cryst.bbk.ac.uk.
authors.forename: Helen R
authors.initials: HR
authors.lastname: Saibil
authors.affiliation: MRC Prion Unit and Department of Neurodegenerative Disease, UCL Institute of Neurology, National Hospital for Neurology and Neurosurgery, Queen Square, London WC1N 3BG, UK j.wadsworth@prion.ucl.ac.uk.
authors.forename: Jonathan D F
authors.identifier: 0000-0002-4797-2259
authors.initials: JD
authors.lastname: Wadsworth
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism*; D006224:Cricetinae; D055032:Electron Microscope Tomography; D051379:Mice; D008958:Models, Molecular; D000072002:Prion Proteins / Q000737:chemistry* / Q000378:metabolism* / Q000648:ultrastructure; D017433:Protein Structure, Secondary
chemical_list: D000072002:Prion Proteins
keywords: electron tomography; prion; prion disease; prion protein; prion structure