The prion protein knockout mouse: a phenotype under challenge - PubMed (original) (raw)

The prion protein knockout mouse: a phenotype under challenge

Andrew D Steele et al. Prion. 2007 Apr-Jun.

Abstract

The key pathogenic event in prion disease involves misfolding and aggregation of the cellular prion protein (PrP). Beyond this fundamental observation, the mechanism by which PrP misfolding in neurons leads to injury and death remains enigmatic. Prion toxicity may come about by perverting the normal function of PrP. If so, understanding the normal function of PrP may help to elucidate the molecular mechansim of prion disease. Ablation of the Prnp gene, which encodes PrP, was instrumental for determining that the continuous production of PrP is essential for replicating prion infectivity. Since the structure of PrP has not provided any hints to its possible function, and there is no obvious phenotype in PrP KO mice, studies of PrP function have often relied on intuition and serendipity. Here, we enumerate the multitude of phenotypes described in PrP deficient mice, many of which manifest themselves only upon physiological challenge. We discuss the pleiotropic phenotypes of PrP deficient mice in relation to the possible normal function of PrP. The critical question remains open: which of these phenotypes are primary effects of PrP deletion and what do they tell us about the function of PrP?

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Figures

Figure 1

Figure 1

The overlap between the normal function of PrPC and the pathogenic dysfunction of PrPSc in disease depicted as a Venn diagram. The extent of overlap between the normal function of PrPC and its role in prion disease is open to speculation, the circles could have a much greater or perhaps even less overlap.

Figure 2

Figure 2

Different approaches to study PrPC's normal function. There are many ways to approach the study of the normal function of PrPC, none of which have conclusively demonstrated PrPC's function. Interacting partners of PrPC have yielded many interesting candidates, human genetic studies have found associations of PrPC with diseases beyond prion disease and even to learning and memory, over- and ectopic-expression studies constitute another approach to determine the function of PrPC, and finally, the focus of this review, the PrP KO has given some clues to the function of PrPC.

Figure 3

Figure 3

A model for the effects of PrPC deletion and deletion mutants of PrPC. (A) Schematic diagram of wild-type PrPC and deletion mutants. SP, signal peptide; octapeptide repeats are indicated in blue; CC, charge cluster; HC, hydrophobic core; H1, H2, H3 Helix 1,2 and 3, respectively; GFP, GPI-anchor addition sequence (B). PrP (black) consists of a globular C-terminal domain (hexagon) and a N-terminal flexible tail (arch) encompassing the octapeptide repeats (ORs) (circle). The model rests on the following assumptions: (1) PrP activates a hitherto unidentified receptor (PrPR) which transmits myelin maintenance signals (flashes); (2) in the absence of PrP, PrPR exerts some residual activity, either constitutively or by recruiting a surrogate ligand; (3) the activity of PrP and its mutants requires homo- or heterodimerization, and induces dimerization of PrPR; and (4) PrP dimers containing PrPΔCD or PrPΔCD trap PrPR in an inactive dominant-negative state. Finally, (5) the OR region stabilizes the interaction between PrP and PrPR, but does not contribute directly to signaling.

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