The clinical presentation of human prion disease varies enormously, and there is considerable overlap observed between individuals with different disease aetiologies [
28,
80,
120,
121] and even in family members with the same pathogenic
PRNP mutation [
29,
31,
32,
65,
77,
80,
125]. Progressive dementia, cerebellar ataxia, pyramidal signs, chorea, myoclonus, extrapyramidal features, pseudobulbar signs, seizures and amyotrophic features can be seen in variable combinations. Criteria used for diagnosis of human prion disease have been defined [
28,
131], and definite diagnosis of sporadic and acquired prion disease relies upon neuropathological examination and the demonstration of abnormal PrP deposition in the central nervous system by either immunoblotting or immunohistochemistry [
20,
28,
60,
128,
131]. Polymorphism at residue 129 of human PrP [encoding either methionine (M) or valine (V)] powerfully affects susceptibility to human prion diseases [
25,
38,
68,
79,
86,
135] with residue 129 acting to directly restrict the propagation of particular prion strains through conformational selection [
26,
27,
30,
119] as well as heterozygosity conferring resistance by inhibiting homologous protein–protein interactions [
25,
30,
86]. About 38% of northern Europeans are homozygous for the more frequent methionine allele, 51% are heterozygous and 11% homozygous for valine. Homozygosity at
PRNP codon 129 predisposes to the development of sporadic and acquired CJD [
25,
38,
68,
79,
86,
135] and is most strikingly observed in vCJD, where all neuropathologically confirmed cases studied so far have been homozygous for codon 129 methionine of
PRNP [
28,
81,
119,
136].
The hypothesis that alternative conformations or assembly states of PrP provide the molecular substrate for a significant part of the clinicopathological heterogeneity seen in human prion diseases and that this relates to the existence of distinct human prion strains is supported by considerable experimental evidence [
30,
34,
90,
113] and also by the demonstration of protein conformation-based inheritance mechanisms of yeast prions [
106,
112,
132]. Different human PrP
Sc isoforms, referred to as molecular strain types, have been identified in the brain of patients with phenotypically distinct forms of CJD [
34,
45,
54,
88,
90,
92,
113,
122,
139] and are classified by both the fragment size and ratio of the three principal PrP bands seen after protease digestion. To date, we have characterised four types of human PrP
Sc that can be commonly identified in sporadic and acquired human prion diseases [
27,
34,
54,
121] (Fig.
1) although much greater heterogeneity seems likely [
121]. Sporadic and iatrogenic CJD and kuru are associated with PrP
Sc types 1-3, while type 4 PrP
Sc is uniquely associated with vCJD and is characterised by a fragment size and glycoform ratio that is similar to PrP
Sc seen in BSE and BSE when transmitted to several other species [
34,
54,
122,
127]. An earlier classification of PrP
Sc types seen in classical CJD described only two banding patterns [
88] with PrP
Sc types 1 and 2 that we describe corresponding with the type 1 pattern of Gambetti and colleagues and our type 3 fragment size corresponding to their type 2 pattern [
87,
90]. Consensus on the nomenclature of human PrP
Sc types has been hindered by the fact that the N-terminal conformation of some PrP
Sc subtypes seen in sporadic CJD can be inter-converted in vitro via changes in metal-ion occupancy [
54,
122] or solvent pH [
21,
84,
138]. While it has proposed that pH alone determines the N-terminal structure of PrP
Sc in sporadic CJD [
21,
84], this interpretation has not been supported by other studies [
69,
98,
122], and the conformations of PrP
Sc types 1 and 2 that we describe in
PRNP methionine homozygous patients show critical dependence upon the presence of copper or zinc ions under conditions, where pH 7.4 is tightly controlled [
122]. While type 4 PrP
Sc is readily distinguished from the PrP
Sc types seen in classical CJD and kuru by a predominance of the di-glycosylated PrP glycoform, type 4 PrP
Sc also has a distinct proteolytic fragment size [
54] although this is not recognised by the alternative classification which designates type 4 PrP
Sc as type 2b [
87].
In addition to the distinct human PrP
Sc types associated with sporadic and acquired prion disease, molecular strain typing has also provided insights into the phenotypic heterogeneity seen inherited human prion diseases [
53,
65]. Patients with inherited prion disease caused by point mutations have glycoform ratios of PrP
Sc fragments distinct from those seen in both classical CJD and vCJD [
53]. Individuals with the same
PRNP mutation can also propagate PrP
Sc with distinct fragment sizes [
53,
96,
97]. Detection of PrP
Sc in the molecular mass range of ca. 21–30 kDa is, however, not a consistent feature, and some cases, in particular those in which amyloid plaques are a prominent feature, show smaller protease resistant fragments of ca. 7–15 kDa [
53,
65,
89,
96,
97,
110]. The propagation of pathological isoforms of wild-type PrP may also make a significant contribution to phenotypic variability in inherited prion disease [
23,
43,
108,
125].