Identification of three novel mutations (E196K, V203I, E211Q) in the prion protein gene (PRNP) in inherited prion diseases with Creutzfeldt-Jakob disease phenotype.
For example, cross-sequence transmission of bovine spongiform encephalopathy (BSE) prions to human generated variant Creutzfeldt-Jakob disease (vCJD) prions which retained the transmissibility to mice expressing bovine PrP.
Paired-pulse stimulation of the Schaffer collaterals evoked hypersynchronous bursting in the hippocampus of vCJD-inoculated mice; comparable bursts were never observed in control or Prnp knockout mice, or in mice inoculated with a strain of prion associated with classical CJD.
This mutation event has been observed to alter the protease activity of the cathepsin D protein and has been linked to an increase in amyloid beta plaque formation in AD. vCJD neuropathology is characterised by the presence of amyloid plaques, formed from the prion protein, and therefore alterations in the amyloid processing activity of cathepsin D may affect the neuropathogenesis of this disease.
In this review I covered recent data on the vCJD and BSE epidemic, the mode of BSE spreading to humans and, finally, the data on the PRNP analogue--the doppel gene (PRND).
Molecular analysis of PrP(Sc) (the scrapie isoform of PrP) from cerebellar tissue demonstrated a novel PrP(Sc) type similar to that seen in vCJD (PrP(Sc) type 4).
The single monkey infected with BASE had a shorter survival, and a different clinical evolution, histopathology, and prion protein (PrPres) pattern than was observed for either classical BSE or vCJD-inoculated animals.
Western blot analysis of PrP(Sc) in the brain in vCJD tissue shows a uniform isotype, with a glycoform ratio characterized by predominance of the diglycosylated band, distinct from sporadic CJD.
These data argue that human PRNP 129 heterozygotes will be more susceptible to infection with vCJD prions than to cattle BSE prions and may present with a neuropathological phenotype distinct from vCJD.
We show that one such technique, protein misfolding cyclic amplification (PMCA), can amplify vCJDPrP(Sc) from human brain tissue, and that the degree of amplification is dependent upon the substrate PRNP codon 129 polymorphism.
Correlation of polydispersed prion protein and characteristic pathology in the thalamus in variant Creutzfeldt-Jakob disease: implication of small oligomeric species.
The presence of abnormal, disease-related prion protein (PrP<sup>D</sup>) has recently been demonstrated by protein misfolding cyclic amplification (PMCA) in urine of patients affected with variant Creutzfeldt-Jakob disease (vCJD), a prion disease typically acquired from consumption of prion contaminated bovine meat.
Besides the molecular typing of protease-resistant PrP in the brain, transmission studies using knock-in mice carrying bovine PrP may aid the differential diagnosis of secondary vCJD infection, especially in individuals with the 129V/V genotype.
Abnormal prion protein (PrP<sup>TSE</sup>) extracted from the brains of vCJD-infected TgBo110 mice displayed different glycosylation profiles and had greater resistance to denaturation by guanidine hydrochloride than PrP<sup>TSE</sup> from infected wild-type mice or from either inoculum.
This minority type 1 PrP(Sc) was found in all 21 cases of variant Creutzfeldt-Jakob disease tested, irrespective of brain region examined, and was also present in the variant Creutzfeldt-Jakob disease tonsil.
Further studies are required to develop more sensitive means of detection of disease-associated prion protein in blood; such techniques could also be employed for screening purposes, both individually and to help ascertain more precisely the likely numbers of future cases of vCJD.
This technique also allows a greatly enhanced sensitivity of detection of disease-associated prion protein in human tissues and fluids, which is potentially applicable to disease screening, particularly for variant Creutzfeldt-Jakob disease.
Here, we report that knock-in mouse expressing humanized chimeric PrP demonstrated PrP(Sc) accumulations in follicular dendritic cells following human prion infections, including variant Creutzfeldt-Jakob disease.
Transfusion transmission of human prion diseases has been observed for variant Creutzfeldt-Jakob disease (vCJD), but not for the classic forms of prion disease (CJD: sporadic, genetic, and iatrogenic).
Recently, we have demonstrated PrP(TSE) in extracellular vesicle preparations (EVs) containing exosomes from plasma of mice infected with mouse-adapted vCJD by Protein Misfolding Cyclic Amplification (PMCA).