NR AOUK
AU Jeffrey,M.J.; Goodsir,C.M.; Race,R.E.; Chesebro,B.
TI Scrapie-induced neurodegeneration is independent of neuronal PrP expression
QU International Conference - Prion diseases: from basic research to intervention concepts - TSE-Forum, 08.10.-10.10.2003, Gasteig, München - Oral sessions OS-22
PT Konferenz-Vortrag
AB In the transmissible spongiform encephalopathies (TSE) accumulation of the abnormal disease-specific prion protein (PrPd) is associated with neurodegeneration. Previous data suggested that PrPd could induce neuronal pathology in brain only when neurons expressed the normal form of PrP (Brandner et al, 1996). However, in vitro experiments indicate that some forms of abnormal PrP are toxic even to PrP-negative neurons. Understanding whether neuronal PrP expression is required for TSE neuropathological damage in vivo is important for determining the mechanism of TSE pathogenesis. Therefore, the present experiments were designed to study scrapie pathogenesis in vivo in the absence of neuronal PrP expression. Hamster scrapie (strain 263K) was used to infect transgenic mice expressing hamster PrP in the brain only in astrocytes. Although these mice were shown previously to develop clinical signs of disease, the association of the abnormal PrP with neuropathology is not known. In the present work both light and electron microscopy identified abnormal PrP mainly around astrocytes, primarily in the extracellular spaces of the neuropil adjacent to the astrocytic plasma membrane, and these neurons demonstrated TSE-specific ultrastructural pathology in spite of lacking PrP expression. Thus, neurodegenerative changes did not require PrP expression on neurons themselves, and disease was not due to a loss of function of neuronal PrP or the intra-neuronal generation of abnormal toxic forms of PrP such as cytoplasmic PrP. Instead, the damage to neurons was more likely mediated by the accumulation of extracellular astrocytic PrPd which was capable of interacting with nearby PrP-negative neurons.
AD Martin J. Jeffrey (m.jeffrey@vla.maff.gov.uk), Caroline M. Goodsir, VLA Lasswade Veterinary Laboratory, Pentlands Science Park, Bush Loan, Penicuik, Edinburgh EH26 OPZ, Scotland, UK; Richard E. Race, Bruce Chesebro, Rocky Mountain Laboratory, Montana, USA
SP englisch
PO Deutschland