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

Malin K. Sandberg, Huda Al-Doujaily, Bernadette Sharps, Michael Wiggins De Oliveira, Christian Schmidt, Angela Richard-Londt, Sarah Lyall, Jacqueline M. Linehan, Sebastian Brandner, Jonathan D. F. Wadsworth, Anthony R. Clarke and John Collinge ()
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Malin K. Sandberg: UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK
Huda Al-Doujaily: UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK
Bernadette Sharps: UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK
Michael Wiggins De Oliveira: UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK
Christian Schmidt: UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK
Angela Richard-Londt: UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK
Sarah Lyall: UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK
Jacqueline M. Linehan: UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK
Sebastian Brandner: UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK
Jonathan D. F. Wadsworth: UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK
Anthony R. Clarke: UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK
John Collinge: UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK

Nature Communications, 2014, vol. 5, issue 1, 1-7

Abstract: Abstract Prions are lethal infectious agents thought to consist of multi-chain forms (PrPSc) of misfolded cellular prion protein (PrPC). Prion propagation proceeds in two distinct mechanistic phases: an exponential phase 1, which rapidly reaches a fixed level of infectivity irrespective of PrPC expression level, and a plateau (phase 2), which continues until clinical onset with duration inversely proportional to PrPC 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 PrPSc at a rate proportional to PrPC 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 PrPC concentration not being rate limiting to exponential prion propagation and neurotoxicity relating to critical concentrations of alternate PrP isoforms whose production is PrPC concentration dependent.

Date: 2014
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DOI: 10.1038/ncomms5347

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