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Prion neuropathology follows the accumulation of alternate prion protein isoforms after infective titre has peaked.

Sandberg, MK; Al-Doujaily, H; Sharps, B; De Oliveira, MW; Schmidt, C; Richard-Londt, A; Lyall, S; ... Collinge, J; + view all (2014) Prion neuropathology follows the accumulation of alternate prion protein isoforms after infective titre has peaked. Nat Commun , 5 , Article 4347. 10.1038/ncomms5347. Green open access

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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.

Type: Article
Title: Prion neuropathology follows the accumulation of alternate prion protein isoforms after infective titre has peaked.
Location: England
Open access status: An open access version is available from UCL Discovery
DOI: 10.1038/ncomms5347
Publisher version: http://dx.doi.org/10.1038/ncomms5347
Language: English
Additional information: © 2014 Macmillan Publishers Limited. All rights reserved. This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Institute of Prion Diseases
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Institute of Prion Diseases > MRC Prion Unit at UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Institute of Prion Diseases > UCL Institute of Prion Diseases Support
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Neurodegenerative Diseases
URI: https://discovery.ucl.ac.uk/id/eprint/1434800
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