NR AWLY
AU Piccardo,P.; King,D.; Campbell,S.; 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 - Poster sessions PA-42
PT Konferenz-Poster
AB The Prion hypothesis predicts that the aetiological agent of the Transmissible Spongiform Encephalopathy (TSE) diseases is an abnormally folded isoform of a host glycoprotein, PrP. This abnormal isoform (PrPsc) is partially proteinase K (PK) resistant, is deposited in infected tissue, and co-purifies with infectivity. Definitive diagnosis of TSE disease and identification of infectivity can only be obtained by transmission studies to mice or other mammals. However these experiments are expensive and time consuming. Current diagnostic methods are therefore based on the detection of the abnormally folded PK-resistant form of PrPsc in post mortem brain tissue, and its identification is taken as indicative of the presence of TSE infectivity. The relationship between PrPsc and TSE infectivity is however still unclear. If PrPsc is not associated with infectivity, its reliability as a diagnostic marker in all cases of disease may be questionable. We have produced transgenic mouse models of TSE disease in which the presence of misfolded forms of PrP and TSE infectivity do not correlate. In gene targeted transgenic mice inoculated with human Gerstmann-Sträussler-Scheinker P102L (GSS P102L) disease (diffuse and amyloid PrP deposition, and spongiform degeneration) or hamster 263K, low or undetectable levels of proteinase K resistant PrP are found in association with high levels of TSE infectivity. Conversely, 101LL transgenic mice inoculated with an atypical isolate of GSS P102L (diffuse and amyloid PrP and no spongiform degeneration) do not develop clinical TSE disease or TSE associated spongiform degeneration during their lifespan. They do however show PrP amyloid accumulation in the sub-callosal region of the brain. Disease observed in 101LL mice with low levels of PrPsc was transmissible to both 101LL and wild type mice, but mice showing only PrP amyloid deposition failed to transmit disease to either 101LL or wild type mice. However, several of the 101LL mice which received the amyloid inoculum were found to contain the same PrP amyloid deposition in the sub-callosal region of the brain. These data suggest that not all abnormal isoforms of PrP are infectious, and that PrP amyloid in particular does not cause a transmissible disease. The reliance on identification of PrPsc in TSE disease diagnosis may therefore be questionable.
AD P.Piccardo: Centre for Biologics Evaluation, FDA, USA, and Indiana University School of Medicine, USA; D. King, S. Campbell, 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