Heterozygous inhibition in prion infection: the stone fence model

Abstract

The human PrP gene (PRNP) has two major polymorphic codons: 129 for methionine (M) or valine (V) and 219 for glutamate (E) or lysine (K). The PRNP heterozygotes appear to be protected from sporadic CJD compared to the PRNP homozygotes. The molecular mechanism responsible for these protective effects of PRNP heterozygosity has remained elusive. In this review, we describe the inhibition of PrP conversion observed in a series of transmission studies using PRNP heterozygous animal models. In vCJD infection, the conversion incompetent human PrP 129V molecules showed an inhibitory effect on the conversion of human PrP 129M molecules in the 129M/V heterozygous mice. Furthermore, though the human PrP 219E and PrP 219K were both conversion competent in vCJD infection, these conversion competent PrP molecules showed an inhibitory effect in the 219E/K heterozygous animals. To explain this heterozygous inhibition, we propose a possible mechanism designated as the stone fence model.

Figure 1

Heterozygous inhibition in vCJD infection. Western blot analysis of PrP^Sc in the spleens of knock-in mice intraperitoneally inoculated with vCJD prions. The amount of PrP^Sc in the 129M/V heterozygous mice was even lower than that in the 129M/0 hemizygous mice. Furthermore, the amount of PrP^Sc was the highest in the 219K/K mice, whereas the PrP^Sc accumulation in the 219E/K heterozygous mice was even lower than that in the 219E/0 hemizygous mice or 219K/0 hemizygous mice. Therefore, we found that both the conversion incompetent PrP and the conversion competent PrP showed inhibitory effects in the heterozygous animals.

Figure 2

The stone fence model: a possible mechanism of the heterozygous inhibition in vCJD infection. PrP^C is converted to PrP^Sc and then piled up into amyloid fibrils according to the nucleated polymerization hypothesis and the trimeric models.– In the homozygous (219E/E or K/K) or the hemizygous (219E/0 or K/0) animals, the PrP^Sc blocks are piled up into the amyloid fibrils without delay because only a uniform PrP^Sc population exists. Though the initial seed is 219E PrP^Sc also in the 219K/K or 219K/0 animals, the resulting 219K PrP^Sc acts as a new seed in the subsequent steps and are efficiently piled up. Therefore, the inhibitory effect of the initial 219E PrP^Sc seed is negligible in these animals. By contrast, in the heterozygous (219E/K) animals, at least two PrP^Sc populations are generated. These two PrP^Sc blocks are piled up into the same fibril just like a stone fence composed of heterologous blocks. The two types of PrP^Sc blocks interfere with each other due to their incompatible structures and delay the fibril elongation. Thus, the distinct PrP^Sc populations act as decelerators of each other in the heterozygous animals.