PrPres and TSE Strains

Strains of TSE agent have been described for CJD (90), scrapie (68,69), and hamster-adapted TME (7). Strains in the TSE are defined by differences in brain pathology, disease incubation time, clinical disease, species tropism, and PrP-res properties (for review, see ref. 19). It is especially challenging to explain TSE strains in terms of PrP-res formation since multiple strains have been described in species with one PrP genotype. It is difficult to imagine how PrP-res with the same amino acid sequence could cause several different disease phenotypes. Since the TSE diseases appear to be diseases of protein folding, however, the answer may reside not in the amino acid sequence but rather in the conformation of the protein. This hypothesis is supported by data from studies using protease digestion of hamster-adapted TME strains (6). If PrP-res can adopt several stable variations in structure, it might be able to pass on its own strain-specific characteristics to PrP-sen via direct PrP-PrP interactions. In fact, recent structural data using infrared spectroscopy (29) or a conformation-dependent immunoassay (118) show that PrP-res from different mouse and hamster TSE strains have different conformations.

3.3.1. PrP-res Conformation and Strains

Two strains of hamster scrapie originally derived from mink infected with TME (7) have provided the best studied example of strain-specific differences in PrP-res conformation. In both strains, PrP-res is derived from the same hamster PrP-sen, but PrP-res derived from hamster brains infected with the "drowsy" strain is approx 1 kDa smaller than PrP-res derived from hamster brains infected with the "hyper" strain (7). When drowsy or hyper PrP-res were mixed with the same radiolabeled PrP-sen precursor in the cell-free conversion system (Fig. 5A), the strain-specific size difference could be detected in the newly made protease-resistant PrP. Thus, protease-resistant PrP generated by drowsy-derived PrP-res was approx 1 kDa smaller than that generated from hyper PrP-res (5,8). In vivo studies using transgenic mice infected with different strains of human CJD also imply that TSE strains may be dependent on the conformation of PrP-res (36,131). Thus, there is evidence to support the hypothesis that self-propagation of PrP-res may proceed via distinctive three-dimensional structures, which in turn could provide some molecular basis for scrapie strains.

3.3.2. PrP-res Glycosylation and Strains

It has also been suggested that PrP-res glycosylation, which can differ between strains (Fig. 5B), might also encode strain-specific phenotypes. However, in vivo studies have suggested that PrP glycosylation does not encode strain characteristics. Strain-specific characteristics are maintained upon transmission of infectivity from one animal to another even when the infected tissues contain PrP-res molecules with very different glycosylation patterns (54,115). The most recent evidence suggests that strain-specific PrP-res glycosylation does not encode strain-specific phenotypes but rather may be indicative of the cellular compartment where the majority of strain-specific PrP-res formation occurs (137).

3.4. PrP-res and Familial TSE

Although there is no correlation with exposure to an infectious agent, TSE agent infectivity is detectable in the brains of individuals afflicted with familial TSE. Intrigu-ingly, PrP-res is also detectable in most familial forms of human TSE, although its size may vary. The question then is how exactly abnormal PrP is generated in familial TSE in the absence of exposure to PrP-res from an exogenous source. Since these diseases are heritable, genetics must play a role. Given the critical role that PrP has in infectious forms of TSE, the most likely genetic component is the PrP gene itself. In fact, familial TSE diseases have been correlated with particular mutations in the PrP gene (Fig. 7) and in most families association of the PrP genotype with onset of disease (i.e. penetrance) is 100%. As seen in Fig. 7, these mutations occur throughout most of the PrP molecule, although many are clustered toward the C-terminus. The current hypothesis is that mutations in the PrP gene lead to a PrP molecule that is more likely to convert spontaneously to the abnormal form. The difference between this type of "spontaneous" conversion and the "induced" conversion associated with exposure to infectivity is that both PrP-sen and PrP-res are derived from the host.

It is now quite clear that mutant PrP molecules have properties different from wildtype PrP and that these altered properties lead to a molecule with properties reminiscent of PrP-res. Insertion of extra copies of an octapeptide repeat in PrP (Fig. 7) has been associated with CJD in several different families and is probably the best studied familial TSE mutant. These mutants are processed differently (39,76) and somewhat resemble PrP-res in that as the number of octapeptide repeats increases they have a greater tendency to aggregate as well as an increased resistance to proteinase K (77,98). Transgenic mice overexpressing one of these mutants even develop a neurological disease (34). Other PrP familial mutations demonstrate different phenotypes. PrP with the Gerstmann-Straussler-Scheinker (GSS)-associated aspartic acid to asparagine mutation at codon 178 shows an altered cell surface expression (92). Mice overexpressing the GSS-associated proline to leucine mutation at codon 102 develop a neurodegenerative disease (62), although transgenic mice expressing wild-type levels of this mutant PrP protein do not (81). Thus, these data suggest that overexpression of the mutant protein may be required for disease. Altered PrP processing has also been linked to a PrP mutation linked to GSS. Mutation of an alanine to a valine at codon 117 results in an increase in transmembrane forms of PrP (79), and transgenic mice overexpressing this PrP mutant develop a neurological disease and are more susceptible to scrapie infection (53).

Although all these studies show that mutant PrP molecules behave differently in vitro and in vivo, the nature of their role in pathogenesis remains unclear. Although most of these PrP mutants are slightly more resistant to proteinase K, their level of resistance is several hundred fold less than that of PrP-res isolated from the brain. In fact, when tested in the cell-free conversion system, PrP mutants containing extra copies of the octapeptide repeat region were unable to form PrP-res spontaneously and were no different from nonmutant PrP in their ability to induce PrP-res formation (98). Thus, despite all these recent advances, the molecular basis for familial TSE remains an open question and may in fact differ for different familial TSEs.

Fig. 7. Mutations in human PrP associated with familial TSE. The structure of human PrP is shown (143). The positions of the signal peptide cleavage at the N-terminus and the GPI anchor addition site at the C-terminus are indicated by the scissors. The open boxes labeled "Repeats" represent an octapeptide sequence that is tandemly repeated five times in normal human PrP. The triple-headed arrows represent the two N-linked glycosylation sites. The asterisks indicate the site of proteinase K cleavage, which can vary somewhat in PrP-res isolated from familial TSE cases. The locations of single amino acid mutations and insertion or deletion mutants associated with familial TSE are indicated (see ref. 48 for review).

Fig. 7. Mutations in human PrP associated with familial TSE. The structure of human PrP is shown (143). The positions of the signal peptide cleavage at the N-terminus and the GPI anchor addition site at the C-terminus are indicated by the scissors. The open boxes labeled "Repeats" represent an octapeptide sequence that is tandemly repeated five times in normal human PrP. The triple-headed arrows represent the two N-linked glycosylation sites. The asterisks indicate the site of proteinase K cleavage, which can vary somewhat in PrP-res isolated from familial TSE cases. The locations of single amino acid mutations and insertion or deletion mutants associated with familial TSE are indicated (see ref. 48 for review).

4. Conclusions

In the study of TSE diseases at both the molecular and pathogenic level, a great many questions remain. For example, how could different conformations of PrP-res lead to different lesion profiles in the brain? Are other molecules involved in PrP-res formation and how could these potential cofactors influence disease? How does the infectious agent enter a cell? For that matter, the question of whether or not PrP-res is actually the infectious agent remains unresolved largely because, owing to the difficulty in purifying or generating new PrP-res, it has never been shown that PrP-res alone can induce disease.

Independent of our understanding the mechanisms of TSE disease, and within the context of the current situation in Great Britain and elsewhere, the most important areas of TSE research are early diagnosis of the disease and development of anti-TSE prophylactic and therapeutic agents. It is still impossible to diagnose CJD in humans prior to the onset of clinical signs, and thus the disease is always fatal. New tests to detect a protein (14-3-3) that is associated with neurological damage (38), the potential for using tonsil biopsy or urinalysis to detect PrP-res prior to the onset of clinical signs (54,125), and a technique to amplify PrP-res (116) are all promising. Identifying effective inhibitors of TSE disease is also of the highest priority. Many different compounds have already been shown to inhibit PrP-res formation and/or delay disease (see ref. 18 for review). Although most of these compounds can delay disease onset, none can actually prevent disease if given just a few days after infection nor can any be used after the onset of clinical signs. The search for rapid diagnostic tests and effective anti-TSE drugs is ongoing and critically important if the threat of TSE as a re-emerging disease is to be overcome.

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