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04.07.2016 | Original Paper | Ausgabe 4/2016 Open Access

Acta Neuropathologica 4/2016

PrP aggregation can be seeded by pre-formed recombinant PrP amyloid fibrils without the replication of infectious prions

Zeitschrift:
Acta Neuropathologica > Ausgabe 4/2016
Autoren:
Rona M. Barron, Declan King, Martin Jeffrey, Gillian McGovern, Sonya Agarwal, Andrew C. Gill, Pedro Piccardo
Wichtige Hinweise

Electronic supplementary material

The online version of this article (doi:10.​1007/​s00401-016-1594-5) contains supplementary material, which is available to authorized users.

Abstract

Mammalian prions are unusual infectious agents, as they are thought to consist solely of aggregates of misfolded prion protein (PrP). Generation of synthetic prions, composed of recombinant PrP (recPrP) refolded into fibrils, has been utilised to address whether PrP aggregates are, indeed, infectious prions. In several reports, neurological disease similar to transmissible spongiform encephalopathy (TSE) has been described following inoculation and passage of various forms of fibrils in transgenic mice and hamsters. However, in studies described here, we show that inoculation of recPrP fibrils does not cause TSE disease, but, instead, seeds the formation of PrP amyloid plaques in PrP-P101L knock-in transgenic mice (101LL). Importantly, both WT-recPrP fibrils and 101L-recPrP fibrils can seed plaque formation, indicating that the fibrillar conformation, and not the primary sequence of PrP in the inoculum, is important in initiating seeding. No replication of infectious prions or TSE disease was observed following both primary inoculation and subsequent subpassage. These data, therefore, argue against recPrP fibrils being infectious prions and, instead, indicate that these pre-formed seeds are acting to accelerate the formation of PrP amyloid plaques in 101LL Tg mice. In addition, these data reproduce a phenotype which was previously observed in 101LL mice following inoculation with brain extract containing in vivo-generated PrP amyloid fibrils, which has not been shown for other synthetic prion models. These data are reminiscent of the “prion-like” spread of aggregated forms of the beta-amyloid peptide (Aβ), α-synuclein and tau observed following inoculation of transgenic mice with pre-formed seeds of each misfolded protein. Hence, even when the protein is PrP, misfolding and aggregation do not reproduce the full clinicopathological phenotype of disease. The initiation and spread of protein aggregation in transgenic mouse lines following inoculation with pre-formed fibrils may, therefore, more closely resemble a seeded proteinopathy than an infectious TSE disease.

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Zusatzmaterial
Supplementary material 1 (PDF 3357 kb)
401_2016_1594_MOESM1_ESM.pdf
Literatur
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