Molecular pathology of human prion disease

Abstract

Human prion diseases are associated with a range of clinical presentations and are classified by both clinicopathological syndrome and aetiology with sub-classification according to molecular criteria. Considerable experimental evidence suggests that phenotypic diversity in human prion disease relates in significant part to the existence of distinct human prion strains encoded by abnormal PrP isoforms with differing physicochemical properties. To date, however, the conformational repertoire of pathological isoforms of wild-type human PrP and the various forms of mutant human PrP has not been fully defined. Efforts to produce a unified international classification of human prion disease are still ongoing. The ability of genetic background to influence prion strain selection together with knowledge of numerous other factors that may influence clinical and neuropathological presentation strongly emphasises the requirement to identify distinct human prion strains in appropriate transgenic models, where host genetic variability and other modifiers of phenotype are removed. Defining how many human prion strains exist allied with transgenic modelling of potentially zoonotic prion strains will inform on how many human infections may have an animal origin. Understanding these relationships will have direct translation to protecting public health.

Fig. 1

Immunoblot analysis of human prion disease brain. a Proteinase K digested brain homogenates analysed with monoclonal antibody 3F4 and enhanced chemiluminescence showing the PrP^Sc types seen in sporadic, acquired and inherited prion disease. Types 1–3 PrP^Sc are seen in the brain of classical forms of CJD (either sporadic or iatrogenic CJD), while type 4 PrP^Sc is uniquely seen in vCJD brain. Distinct PrP^Sc types are seen in cases with PRNP point mutations. Classification according to Hill et al. [53, 54]. b Proteinase K digestion of brain homogenate and analysis with anti-PrP monoclonal antibody 3F4 by enhanced chemifluorescence enables calculation of the proportions of di-, mono-, and non-glycosylated PrP. The key shows PrP^Sc type or mutation and PRNP codon 129 genotype (M methionine, V valine). Data points represent the mean relative proportions of di- and mono-glycosylated PrP as percentage ± SEM. In some cases, the error bars were smaller than the symbols used

Fig. 2

Distinct patterns of PrP deposition in brain in human prion disease. The disease aetiology, PRNP codon 129 genotype of the patient (M methionine, V valine) and the type of PrP^Sc detected in each sample (using the London classification of human PrP^Sc types [54]) is designated above each brain sample. The most common subtype of sporadic CJD (a) typically shows a diffuse, synaptic pattern of abnormal PrP deposition, while kuru (b) shows not only variably diffuse PrP deposition but also striking formation of PrP plaques in various areas of the brain. These PrP plaques are consistently distinct from those seen in vCJD (c), where PrP plaques are often surrounded by conspicuous vacuolation, designated ‘florid plaques’. Scale bars a, c 25 μm; b 50 μm