The prion protein knockout mouse: a phenotype under challenge

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?

Figure 1

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

Figure 2

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

Figure 3

A model for the effects of PrP^C deletion and deletion mutants of PrP^C. (A) Schematic diagram of wild-type PrP^C 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 (PrP_R) which transmits myelin maintenance signals (flashes); (2) in the absence of PrP, PrP_R 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 PrP_R; and (4) PrP dimers containing PrP_ΔCD or PrP_ΔCD trap PrP_R in an inactive dominant-negative state. Finally, (5) the OR region stabilizes the interaction between PrP and PrP_R, but does not contribute directly to signaling.