Altered trafficking of abnormal prion protein in atypical scrapie: Prion protein accumulation in oligodendroglial inner mesaxons

Prion diseases are fatal neurodegenerative diseases of man and animals that have been recognised for hundreds of years and are characterised by disease specific accumulations of a host membrane sialoglycoprotein known as prion protein (PrPd). In all classical forms of prion disease, PrPd accumulates in the extracellular space as fibrillar amyloid, intra-cellularly within lysosomes, but mainly on membranes where it is associated with unique and characteristic membrane pathology. These membrane changes are found in all species and strains of natural and experimental classical forms of prion disease and consist of spiral, branched and clathrin coated membrane invaginations on dendrites. Increased surveillance for prion disease following the bovine spongiform encephalopathy epidemic has led to the recognition of atypical prion disease. Atypical scrapie of sheep has distinct biological, biochemical and pathological properties when compared to classical scrapie. Immunohistochemical PrPd accumulations in atypical scrapie are characterised mainly by diffuse punctate accumulation in grey matter and a distinctive white matter accumulation. Using immunogold electron microscopy, we describe here the sub-cellular patterns of PrPd accumulation in atypical scrapie affected sheep and tg338 mice. Classical prion-disease associated membrane lesions were not found in atypical scrapie affected sheep, however, white matter PrPd accumulation was localised mainly to the inner mesaxon and paranodal cytoplasm of oligodendroglia. Similar lesions were found in myelinated axons of atypical scrapie tg338 infected mice. However, tg338 mice also showed the unique grey matter membrane changes seen in other classical forms of disease. These data show that atypical scrapie infection directs a change in the trafficking of abnormal PrP to axons and oligodendroglia and also that the resulting pathology is an interaction between the agent strain and host genotype.