Membrane Toxicity of Abnormal Prion Protein in Adrenal Chromaffin Cells of Scrapie Infected Sheep

Abstract

Transmissible spongiform encephalopathies (TSEs) or prion diseases are associated with accumulations of disease specific PrP (PrPd) in the central nervous system (CNS) and often the lymphoreticular system (LRS). Accumulations have additionally been recorded in other tissues including the peripheral nervous system and adrenal gland. Here we investigate the effect of sheep scrapie on the morphology and the accumulation of PrPd in the adrenal medulla of scrapie affected sheep using light and electron microscopy. Using immunogold electron microscopy, non-fibrillar forms of PrPd were shown to accumulate mainly in association with chromaffin cells, occasional nerve endings and macrophages. PrPd accumulation was associated with distinctive membrane changes of chromaffin cells including increased electron density, abnormal linearity and invaginations. Internalisation of PrPd from the chromaffin cell plasma membrane occurred in association with granule recycling following hormone exocytosis. PrPd accumulation and internalisation from membranes is similarly associated with perturbations of membrane structure and trafficking in CNS neurons and tingible body macrophages of the LRS. These data suggest that a major toxic effect of PrPd is at the level of plasma membranes. However, the precise nature of PrPd-membrane toxicity is tissue and cell specific suggesting that the normal protein may act as a multi-functional scaffolding molecule. We further suggest that the co-localisation of PrPd with exocytic granules of the hormone trafficking system may provide an additional source of infectivity in blood.