Research Article: Transmission characteristics of heterozygous cases of Creutzfeldt-Jakob disease with variable abnormal prion protein allotypes

Date Published: June 9, 2020

Publisher: BioMed Central

Author(s): Anne Ward, Jason R. Hollister, Kristin McNally, Diane L. Ritchie, Gianluigi Zanusso, Suzette A. Priola.


In the human prion disease Creutzfeldt-Jakob disease (CJD), different CJD neuropathological subtypes are defined by the presence in normal prion protein (PrPC) of a methionine or valine at residue 129, by the molecular mass of the infectious prion protein PrPSc, by the pattern of PrPSc deposition, and by the distribution of spongiform change in the brain. Heterozygous cases of CJD potentially add another layer of complexity to defining CJD subtypes since PrPSc can have either a methionine (PrPSc-M129) or valine (PrPSc-V129) at residue 129. We have recently demonstrated that the relative amount of PrPSc-M129 versus PrPSc-V129, i.e. the PrPSc allotype ratio, varies between heterozygous CJD cases. In order to determine if differences in PrPSc allotype correlated with different disease phenotypes, we have inoculated 10 cases of heterozygous CJD (7 sporadic and 3 iatrogenic) into two transgenic mouse lines overexpressing PrPC with a methionine at codon 129. In one case, brain-region specific differences in PrPSc allotype appeared to correlate with differences in prion disease transmission and phenotype. In the other 9 cases inoculated, the presence of PrPSc-V129 was associated with plaque formation but differences in PrPSc allotype did not consistently correlate with disease incubation time or neuropathology. Thus, while the PrPSc allotype ratio may contribute to diverse prion phenotypes within a single brain, it does not appear to be a primary determinative factor of disease phenotype.

Partial Text

Prion diseases are fatal, transmissible neurodegenerative diseases of mammals that are associated with the misfolding of a normally protease-sensitive and soluble protein called prion protein or PrPC, into a partially protease-resistant, insoluble and infectious form termed PrPSc [18]. Accumulation of PrPSc in the brain over time, as large amyloid or non-amyloid aggregates, eventually leads to clinical prion disease and death. In humans, prion diseases can be hereditary, sporadic, or acquired. In hereditary prion diseases, mutations in the prion protein (PRNP) gene are associated with different types of prion disease such as Gerstmann-Sträussler-Scheinker syndrome, fatal familial insomnia, and genetic Creutzfeldt-Jakob disease [26]. Sporadic Creutzfeldt-Jakob disease (sCJD), which is thought to arise as the result of spontaneous misfolding of PrPC in the brain into infectious PrPSc, is the most common form of human prion disease and occurs at an incidence of approximately1–2 cases per million people worldwide. Acquired forms of prion disease can result from the ingestion of prion contaminated tissue, as was the case with variant CJD which has been linked to ingestion of bovine spongiform encephalopathy (BSE) contaminated products, and kuru, which was the result of the cannibalistic practices of the Fore tribe in New Guinea. They can also result from exposure to prion contaminated medical instruments, devices or products such as dura mater grafts, pituitary gland derived human growth hormone, and human blood and blood products. Collectively, these latter forms of acquired prion disease are known as iatrogenic CJD (iCJD) [22].

In transgenic mice expressing only human PrPC-M129, a mismatch at amino acid 129 in the inoculum can influence disease incubation time. Thus, the MM1 subtype of sCJD transmits most efficiently into transgenic mice homozygous for human PrPC-M129 [2, 5, 25, 43]. However, transmission of MV heterozygous cases of CJD can vary by incubation time and CJD type [5, 20, 23, 25, 44]. Our hypothesis was that the variable transmission efficiency of heterozygous cases of sCJD into transgenic mice expressing human PrPC-M129 was determined by the PrPSc allotype ratio in the sample inoculated. Our expectation was therefore that MV heterozygous CJD samples with statistically higher levels of PrPSc-M129 would transmit disease more efficiently into our mice than samples where PrPSc-V129 predominated. This hypothesis was supported by data from two of the sCJD subtypes we tested, MV1 + 2C and MV2K, but did not hold true for the MV2K + 2C subtype. In the latter subtype, a greater abundance of PrPSc-M129 in the sample relative to PrPSc-V129 led to prolonged incubation times and had a negative effect on disease transmission. Thus, our data suggest that the relative amount of PrPSc-M129 in cases of heterozygous CJD is not predictive of disease incubation time even when the amino acid at codon 129 is the same in both the inoculum and host.

PrPSc allotype is not predictive of disease incubation time and is not the primary determinative driver of phenotype in heterozygous cases of CJD. However, it does appear to correlate with the type of PrPSc deposited. Thus, when PrPSc-V129 predominates, PrPSc plaques are common. We further conclude that, within a single patient brain, prions with different infectious properties can arise in brain regions with different PrPSc allotypes. These data may help to explain why multiple prion strains can be isolated from a single brain. Finally, we conclude that MV2K prions from sCJD differ from iCJD MV2K prions, suggesting that sCJD MV2K may not have been the source of infection in human growth hormone related cases of iCJD in the UK. Overall, our data demonstrate that there is more heterogeneity in the transmission properties of CJD neurological subtypes than has been previously described and suggest a complex picture of CJD transmission where CJD subtype, PrPSc conformation, PrPSc allotype, and the host likely all contribute to the final disease phenotype.