It is remarkable how many distinct misfolded conformations PrP can take on. We know of the different genetic phenotypes (CJD, FFI, GSS) in humans, but most sporadic cases have been classified as sCJD. Zou 2010, of Case Western, points us to yet a new strain of sporadic prion disease distinct from sCJD in both phenotype and biochemical properties. The disease course is longer (22-45 months) than sCJD, and the biochemical properties of the misfolded PrP are different (not always proteinase K resistant, hence “variably proteinase sensitive prionopathy”. Yet even within this VPSPr category, there are subtler differences in both phenotype and biochemistry according to codon 129 genotype:
Significant clinical differences among the 129VV and 129MV groups (only 2 129MM symptomatic subjects were available) occurred in the mean age at onset and in disease duration (see Table). PrP immunostaining patterns were also distinguishable in the 3 groups… These findings also indicate that, in the present series of cases, it is the 129 genotype that modifies the phenotypic characteristics, including PK resistance and antibody immunoreactivity of PrPDis.
What’s more, while these were sporadic cases with no mutations in the PRNP gene, there is some evidence of familial histories of dementia in several of the cases, which the authors take to suggest that VPSPr may have genetic risk factors. It also looks as though VPSPr may be difficult to transmit to wild type animals. You’ll recall that Mastrianni’s group at U. Chicago experiments on genetic mouse models of GSS, however, GSS is unique among prion diseases in that the misfolded proteins appear to not “recruit” wild-type proteins. (Aside: I still have to figure out how, then, the Fukuoka-1 mouse prion strain was derived from GSS as mentioned by Kawasaki 2007. Googling only led to Arima 2005 who cites Tateishi 1979 who is actually writing about kuru). Anyway, it also appears to also be the case that VPSPr is not easily transmissible, and so the authors point to the possibility that VPSPr may be seen as sporadic GSS:
Experiments on the transmissibility of VPSPr are ongoing. Preliminary data indicate that VPSPr transmissibility, if it occurs at all, is not efficient, and it could be more like that of GSS-P102L associated with PrPDis 7kDa or of PK-sensitive PrP amyloid fibers, which require long incubation times and do not shorten the life span of the affected animals… It is intriguing that GSS also shows characteristics of the phenotype and of the PrPDis associated with some of the mutations that resemble those of VPSPr.25 They include long disease duration, multiple PK-resistant fragments, and variable PK resistance of PrPDis. Our comparative analysis of the electrophoretic profiles in VPSPr and GSS-A117V reveals provocative similarities. This finding raise the issue of whether VPSPr might be viewed as the sporadic form of GSS.
In general, the fact that there are so many distinct diseased conformations of PrP suggests that drugs which act by direct interaction with PrP will have highly strain-specific efficacy, as seen with cpd-B. By contrast, drugs which act by enhancing the cell’s ability to clear misfolded proteins (perhaps rapamycin) may be expected to act more broadly on different diseases. This issue will also be the theme of a forthcoming post reviewing a review of antiprion compounds.