Prion neurotoxicity: insights from prion protein mutants

Abstract

The chemical nature of prions and the mechanism by which they propagate are now reasonably well understood. In contrast, much less is known about the identity of the toxic prion protein (PrP) species that are responsible for neuronal death, and the cellular pathways that these forms activate. In addition, the normal, physiological function of cellular PrP (PrP(C)) has remained mysterious, hampering efforts to determine whether loss or alteration of this function contributes to the disease phenotype. Considerable evidence now suggests that aggregation, toxicity, and infectivity are distinct properties of PrP that do no necessarily coincide. In this review, we will discuss several mutant forms of PrP that produce spontaneous neurodegeneration in humans and/or transgenic mice without the formation of infectious PrP(Sc). These include an octapeptide insertional mutation, point mutations that favor synthesis of transmembrane forms of PrP, and deletions encompassing the central domain whose neurotoxicity is antagonized by the presence of wild-type PrP. By isolating the neurotoxic effects of PrP from the formation of infectious prions, these mutants have provided important insights into possible pathogenic mechanisms. These studies suggest that prion neurotoxicity may involve subversion of a cytoprotective activity of PrP(C) via altered signaling events at the plasma membrane.

FIGURE 1. Schematic of wild-type and mutant PrP molecules, Doppel, and Shadoo

Structural domains are indicated by the colored blocks: SS (yellow), signal sequence; OR (green), octapeptide repeats; HD (blue), hydrophobic domain; GPI (red), glycosyl-phosphatidylinositol attachment signal; R/G (pink), arginine/glycine repeats of Sho. The lollipop symbols indicate sites of N-linked glycosylation, and the S—S symbols indicate disulfide linkages.

FIGURE 2. Model for the neuroprotective activity of PrP^C, and subversion of this activity by neurotoxic forms of PrP

The structured, C-terminal half of PrP is shown in green and the flexible, N-terminal tail as a blue line. The CR segment of PrP (residues 105–125) is shown as a red rectangle. Tr, hypothetical signal transducing protein that normally generates a neuroprotective signal (solid pink), but which can assume an altered conformation (crosshatched pink) that generates a neurotoxic signal. Two binding sites between PrP and Tr are shown, one involving the C-terminal half of PrP and the other CR segment of PrP. When both binding sites are occupied, Tr elicits a non-essential neuroprotective signal (PrP^C). When only the C-terminal site is occupied, as would be the case when the CR segment is absent (PrPΔCR), embedded in the lipid bilayer (^CtmPrP), or conformationally altered (PG14 and PrP^Sc), the transducer delivers a neurotoxic signal. The toxicity of ^CtmPrP requires the cooperation of wild-type PrP^C.