10 Cell Biology of Prions

Abstract

The cellular prion protein (PrP^C) is a cell-surface glycoprotein anchored by a glycosylphosphatidylinositol (GPI) moiety (Stahl et al. 1987). PrP^C is expressed throughout the brain, particularly in neurons (Kretzschmar et al. 1986;Moser et al. 1995), and to a lesser extent in extraneural tissues (Bendheim et al. 1992; Ford et al. 2002). In the prion diseases, PrP^C is converted to an abnormal, conformationally altered isoform (PrP^Sc), which subsequently accumulates in the brain and results in extensive neurodegeneration with an inevitably fatal outcome (Prusiner 1996). Therefore, localizing PrP^C in the brain is an important step in understanding the biology of the normal protein and in mapping changes in models of experimental prion diseases.

EXPRESSION AND LOCALIZATION OF PrP ^C IN BRAIN
The precise localization of PrP^C remains enigmatic, due to conflicting data obtained using different techniques. Immunohistochemical studies have described a somatic expression of PrP^C in neurons with no or only a minor signal in the neuropil (DeArmond et al. 1987; Piccardo et al. 1990; Safar et al. 1990; Bendheim et al. 1992; Verghese-Nikolakaki et al. 1999; Ford et al. 2002). Contradictory findings probably reflect the peculiarities inherently associated with pre-embedding techniques. Many immunoelectron microscopic procedures may result in a destruction of cellular membranes, possibly leading to an artificial redistribution of GPI-anchored proteins within the membrane.

These uncertainties with regard to the precise subcellular localization of PrP^C therefore encouraged two of us (P.J.P. and S.B.P.) to perform a quantitative study of the ultrastructural localization of PrP^C in the mouse brain. We used a...