NR AXPE
AU Jeffrey,M.J.
TI Cellular Pathology of Prion Diseases
QU International Conference - Prion 2007 (26.-28.9.2007) Edinburgh International Conference Centre, Edinburgh, Scotland, UK - Book of Abstracts: Invited Speakers S3.1
IA http://www.prion2007.com/pdf/Prion Book of Abstracts.pdf
PT Konferenz-Vortrag
AB
Immunohistochemistry of scrapie and other prion disease infected tissues shows that disease associated accumulations of the prion protein (PrPd) occurs in a range of morphological types which differs according to the species, strain, tissue and cell type. It is postulated that such accumulations in brain are the cause of neurological disease and that different tertiary or quaternary structures of infectious isoforms of prion protein provide the information necessary to code for strain properties. We have determined the cellular pathology of PrPd accumulation using immunogold electron microscopy for several experimental strains of murine scrapie, and for naturally occurring ovine scrapie, BSE of cattle and FSE of cats.
In sheep scrapie brains PrPd accumulation corresponded ultrastructurally with abnormal clathrin and ubiquitin mediated endocytosis, increased number of endolysosomes, microfolding of plasma-membranes, extracellular PrPd release and intercellular PrPd transfer between neurons and, or glia. When different sheep or murine scrapie strains are compared, the same accumulation types of PrPd and associated sub-cellular lesions are present in all strains examined although in different proportions. Similarly natural BSE and FSE show different proportions of same PrPd types and lesions.
Scrapie infected lymphoid tissues show cell membrane changes of follicular dendritic cells (FDCs) and macrophages. PrPd accumulation is associated with increased retention of immune complexes on FDCs and with internalised cell membrane PrPd via an abnormal endocytosis mechanism in macrophages morphologically similar to that seen in neurons. By contrast the cell membrane internalisation of macrophage PrPd is via a non-clathrin mediated mechanism.
We conclude that:
a) The main toxic effects of PrPd are seen at the cell membrane and are not primarily due to its accumulation in the cytoplasm.
b) The trafficking pathways of PrPd depend on strain and cell type,
c) A single prion strain provokes several different pathological PrPd membraneprotein-interactions implying individual prion strains consist of, or result in, accumulation of a variety of PrPd forms rather than a single entity. Potentially, different strains may be encoded by different proportions of the same PrPd isoforms.
AD Martin Jeffrey, Veterinary Laboratories Agency Lasswade, Penicuik, UK
SP englisch
PO Schottland