To the editor:

In a recently published article1, Paramithiotis et al. describe antibodies specific for the prion Tyr-Tyr-Arg (YYR) repeat motif. These antibodies interact with the pathological isoform of the prion protein (PrPSc), but not with the normal cellular isoform (PrPC). Because of this restricted specificity, they suggest that YYR-specific antibodies could be useful for the diagnosis and treatment of prion diseases (Fig. 1). The monoclonal antibodies, all of the IgM isotype, were produced by immunizing mice with a synthetic peptide (CYYRRYYRYY). When coupled to magnetic beads, these YYR-specific antibodies immunoprecipitate PrPSc much more efficiently than PrPC. Notably, the Paramithiotis study did not rely on antibodies to YYR for specific detection of PrP. Their immunoblots were not ultimately probed with PrPSc-specific antibodies, but rather with 'regular' antibodies. The latter can detect PrP (but do not distinguish between PrPSc and PrPC) in a precipitate that could include any protein containing solvent-accessible tyrosine and arginine residues.

Figure 1: Conversion of the normal form of the prion protein (PrPC) to the pathogenic form (PrPSc) produces protein aggregates such as these.
figure 1

Courtesy of Adriano Aguzzi and Markus Glatzel

Scale bar, 20 μm.

Full size image

This report is notably similar to that of Korth et al.2, who described a PrpSc-specific IgM (designated 15B3) after immunizing with full-length recombinant bovine PrP. The 15B3 epitope consists of three separate, linear segments of PrP (15B3-1, 15B3-2 and 15B3-3). The YYR epitope (bold) identified by Paramithiotis et al. is included in or located near two of the 15B3 segments (underlined): GSDYEDR YYR (15B3-1) and YYR PVDQYS (15B3-2). Thus, these two independent studies relying on the same method of immunoprecipitation have identified similar IgM antibodies interacting with the same region on PrP, and possibly with the same YYR motifs.

The new reagents described could put an end to the quest for a PrPSc-specific antibody. Because the authors envision therapeutic use of the described antibodies, however, it seems appropriate to emphasize that YYR-specific antibodies could interact with any protein with tyrosine and arginine residues on its surface. In regard to PrPSc detection, it should be noted that no diagnostic application of 15B3 has been reported since the report of Korth et al. was published in in 1997. The availability of new diagnostic tests sensitive enough to ensure the protection of public health is an important issue3. For the design of such tests, there remains the choice between high-affinity antibodies that recognize both PrPSc and PrPC but require prior elimination of PrPC, and lower-affinity but PrPSc-specific antibodies.

See Reply to “Properties of a disease-specific prion probe” by Paramithiotis et al.