NR AWLX
AU Piccardo,P.; King,D.; Ghetti,B.; Manson,J.C.; Barron,R.M.
TI Deposition of PrP amyloid in the absence of transmissible disease
QU International Conference - Prion 2006: Strategies, advances and trends towards protection of society - 3.10.-6.10.2006, Torino, Italy, Lingotto Conference Centre - Oral sessions ORAL-39
PT Konferenz-Vortrag
AB The Prion hypothesis predicts that the aetiological agent of TSE disease is an abnormally folded isoform of a host glycoprotein, PrP. All current EU approved TSE diagnostic assays are based on the detection of this abnormal proteinase K (PK) resistant protein (PrPsc) in post mortem brain tissue, and its identification is taken as indicative of the presence of TSE infectivity. However, the relationship between PrPsc and TSE infectivity is still unclear, and it is unknown which particular isoform of PrPsc (PK-res, PK-sen, amyloid) is infectious. Gerstmann-Sträussler-Scheinker P102L (GSS P102L) disease is an autosomal dominant human TSE characterised by the accumulation of PrP amyloid in the brain. Two phenotypically distinct forms of GSS P102L exist, both have diffuse PrP and PrP amyloid plaques, but only one has spongiform degeneration. We present results of studies designed to determine whether a pathogenic PrP species that is not infectious exits in GSS P102L. We have inoculated brain extracts from GSS P102L of both phenotypes into gene targeted transgenic (Tg) mice expressing the equivalent mutation (P101L) in murine PrP. Brain extracts from a patient with diffuse and amyloid PrP deposition and spongiform degeneration transmitted 100% to 101LL Tg mice (290d), but extracts from a patient with diffuse and amyloid PrP and no spongiform degeneration transmitted inefficiently (1/22) with animals surviving over 600 days. However several non clinical mice lacking disease associated vacuolation had PrP plaques in the sub-callosal region of the brain. Brain homogenate from such mice failed to transmit disease on subpass in 101LL Tg and wild type mice, and no disease associated vacuolation or diffuse PrP deposition was found on pathological examination. However the 101LL but not wild type mice showed PrP plaques in the same region as previously observed. These data suggest that PrP amyloid is neither neurotoxic nor infectious, and its presence does not cause the development of TSE disease.
AD P.Piccardo: Centre for Biologics Evaluation, FDA, USA and Indiana University School of Medicine, USA; D. King, J.C. Manson, R.M. Barron: Institute for Animal Health, NPU, Edinburgh, UK; B.Ghetti: Indiana University School of Medicine, USA. E-mail: rona.barron@bbsrc.ac.uk
SP englisch
PO Italien