Abstract
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.
Highlights
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 normal prion protein (PrPC), into a partially protease-resistant, insoluble and infectious form termed infectious prion protein (PrPSc) [18]
We have recently shown that the PrPSc allotype ratio is variable in MV1 and MV2 cases of Sporadic CreutzfeldtJakob disease (sCJD) but somewhat less variable in cases of MV2K iatrogenic Creutzfeldt-Jakob disease (CJD) (iCJD) in the United Kingdom (UK) [28] that were the result of exposure to prion contaminated human growth hormone derived from cadavers
Brain homogenate samples from the cerebral cortex (CC) or the cerebellar cortex (CbC) were inoculated intracranially into two different strains of transgenic mice over-expressing human PrPC-M129 [37], tgRM and tg66. Since both mouse strains are homozygous for PrPC-M129, we hypothesized that they would be more susceptible to heterozygous CJD isolates containing
Summary
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]. Ward et al Acta Neuropathologica Communications (2020) 8:83 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 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. Based on all of these criteria, there are currently believed to be 6 major subtypes or strains of sCJD (in order of frequency): MM1/MV1, VV2, MV2K (i.e. Type 2 PrPSc with the “K” designating kuru-type plaques), MM2T (thalamic), MM2C (cortical), and VV1 [3]
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