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10 Cell Biology of Prions

David A. Harris, Peter J. Peters, Albert Taraboulos, Vishwanath Lingappa, Stephen J. Dearmond, Stanley B. Prusiner


The cellular prion protein (PrPC) is a cell-surface glycoprotein anchored by a glycosylphosphatidylinositol (GPI) moiety (Stahl et al. 1987). PrPC 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, PrPC is converted to an abnormal, conformationally altered isoform (PrPSc), which subsequently accumulates in the brain and results in extensive neurodegeneration with an inevitably fatal outcome (Prusiner 1996). Therefore, localizing PrPC 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.

The precise localization of PrPC remains enigmatic, due to conflicting data obtained using different techniques. Immunohistochemical studies have described a somatic expression of PrPC 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 PrPC therefore encouraged two of us (P.J.P. and S.B.P.) to perform a quantitative study of the ultrastructural localization of PrPC in the mouse brain. We used a...

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