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Abstract
Human P102L Gerstmann-Sträussler-Scheinker (GSS) disease is a familial TSE which is associated with a single amino acid mutation at codon 102 in human PrP. However, two distinct phenotypes of disease are associated with this single amino acid mutation. In classical P102L GSS (PrP-21) amyloid plaques and diffuse PrP deposition are accompanied by spongiform degeneration of the brain and the presence of PrP 27-30. In atypical forms of P102L GSS (PrP-8), amyloid deposition occurs in the absence of any spongiosis, and only an 8kDa PrP-res band is observed on immunoblot. While inoculation of PrP-21 can transmit TSE disease to transgenic mice homozygous for the equivalent mutation in murine PrP (101LL; courtesy of Prof J Manson, Edinburgh), inoculation of 101LL mice with PrP-8 results mainly in the production of further PrP amyloid without any associated clinical signs or spongiform degeneration. Subsequent subpassages produced further amyloid seeding but no disease. These data indicate that PrP amyloid may be seeded in the brain of 101LL mice in the absence of TSE disease or replication of infectivity. To further investigate this seeding mechanism we have utilised recombinant PrP (Prnpa and Prnpa-101L) refolded into three different conformations (α-monomeric, β-oligomeric or fibril amyloid) and inoculated this material into both 101LL and WT mice. No PrP aggregation was observed following inoculation of α-monomeric or β-oligomeric PrP isoforms; however PrP amyloid inoculations exhibited seeding of amyloid plaques in 101LL but not Wt mice with both 101L and Wt fibril amyloid preps. We clearly demonstrate here that abnormal forms of PrP can exist in the brain without causing a spongiform encephalopathy. PrP misfolding can therefore be separated from propagation of TSE infectivity as PrP amyloid accumulation can be induced in 101LL transgenic mice in the absence of infected inoculum.
Original language | English |
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Pages (from-to) | 27 |
Journal | Prion |
Volume | 8 |
Issue number | Suppt. |
Publication status | Published - 27 May 2014 |
Event | Prion 2014 - Trieste, Italy, United Kingdom Duration: 24 May 2014 → 30 Jun 2014 |
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- 2 Finished
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Livestock neurobiology
Gill, A., Barron, R., Beard, P., Brunton, P., Goldmann, W., Hume, D., Hunter, N., Lawrence, A., Mabbott, N., Manson, J., McColl, B., Meddle, S. & Wishart, T.
1/04/12 → 31/03/17
Project: Research
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Accumulation of PrP amyloid in vivo that is not infectious
Barron, R.
1/05/08 → 28/02/11
Project: Research