title: Prion neuropathology follows the accumulation of alternate prion protein isoforms after infective titre has peaked.
abstract: Prions are lethal infectious agents thought to consist of multi-chain forms (PrP(Sc)) of misfolded cellular prion protein (PrP(C)). Prion propagation proceeds in two distinct mechanistic phases: an exponential phase 1, which rapidly reaches a fixed level of infectivity irrespective of PrP(C) expression level, and a plateau (phase 2), which continues until clinical onset with duration inversely proportional to PrP(C) expression level. We hypothesized that neurotoxicity relates to distinct neurotoxic species produced following a pathway switch when prion levels saturate. Here we show a linear increase of proteinase K-sensitive PrP isoforms distinct from classical PrP(Sc) at a rate proportional to PrP(C) concentration, commencing at the phase transition and rising until clinical onset. The unaltered level of total PrP during phase 1, when prion infectivity increases a million-fold, indicates that prions comprise a small minority of total PrP. This is consistent with PrP(C) concentration not being rate limiting to exponential prion propagation and neurotoxicity relating to critical concentrations of alternate PrP isoforms whose production is PrP(C) concentration dependent.
authors.affiliation: MRC Prion Unit and Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
authors.forename: Malin K
authors.initials: MK
authors.lastname: Sandberg
authors.affiliation: MRC Prion Unit and Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
authors.forename: Huda
authors.initials: H
authors.lastname: Al-Doujaily
authors.affiliation: MRC Prion Unit and Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
authors.forename: Bernadette
authors.initials: B
authors.lastname: Sharps
authors.affiliation: MRC Prion Unit and Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
authors.forename: Michael Wiggins
authors.initials: MW
authors.lastname: De Oliveira
authors.affiliation: MRC Prion Unit and Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
authors.forename: Christian
authors.initials: C
authors.lastname: Schmidt
authors.affiliation: MRC Prion Unit and Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
authors.forename: Angela
authors.initials: A
authors.lastname: Richard-Londt
authors.affiliation: MRC Prion Unit and Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
authors.forename: Sarah
authors.initials: S
authors.lastname: Lyall
authors.affiliation: MRC Prion Unit and Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
authors.forename: Jacqueline M
authors.initials: JM
authors.lastname: Linehan
authors.affiliation: MRC Prion Unit and Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Brandner
authors.affiliation: MRC Prion Unit and Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
authors.forename: Jonathan D F
authors.initials: JD
authors.lastname: Wadsworth
authors.affiliation: MRC Prion Unit and Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
authors.forename: Anthony R
authors.initials: AR
authors.lastname: Clarke
authors.affiliation: MRC Prion Unit and Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
authors.forename: John
authors.initials: J
authors.lastname: Collinge
mesh_terms: D000818:Animals; D005260:Female; D006801:Humans; D007700:Kinetics; D051379:Mice; D018621:PrPC Proteins / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity*; D018620:PrPSc Proteins / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity; D017096:Prion Diseases / Q000378:metabolism*
chemical_list: D018621:PrPC Proteins; D018620:PrPSc Proteins