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

Abstract

Prion diseases exist in classical and atypical disease forms. Both forms are characterized by disease-associated accumulation of a host membrane sialoglycoprotein known as prion protein (PrPd ). In classical forms of prion diseases, PrPd can accumulate in the extracellular space as fibrillar amyloid, intracellularly within lysosomes, but mainly on membranes in association with unique and characteristic membrane pathology. These membrane changes are found in all species and strains of classical prion diseases and consist of spiral, branched and clathrin-coated membrane invaginations on dendrites. Atypical prion diseases have been described in ruminants and man and have distinct biological, biochemical and pathological properties when compared to classical disease. The purpose of this study was to determine whether the subcellular pattern of PrPd accumulation and membrane changes in atypical scrapie were the same as those found in classical prion diseases. Immunogold electron microscopy was used to examine brains of 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 localized 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 classical forms of disease. These data show that atypical scrapie infection directs a change in trafficking of abnormal PrP to axons and oligodendroglia and that the resulting pathology is an interaction between the agent strain and host genotype.