Human prion diseases and bovine spongiform encephalopathy (BSE)
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1997 Oxford University Press Human Molecular Genetics, 1997, Vol. 6, No. 10 Review 1699–1705
Human prion diseases and bovine spongiform
encephalopathy (BSE)
John Collinge
Prion Disease Group, Neurogenetics Unit, Imperial College School of Medicine at St. Mary’s, London, UK
Received July 11, 1997
Prion diseases are transmissible neurodegenerative disorders which affect a range of mammalian species. In
humans they can be inherited and sporadic as well as acquired by exposure to human prions. Prions appear to
be composed principally of a conformational isomer of host-encoded prion protein and propagate by recruitment
of cellular prion protein. Recent evidence argues that prion protein can also encode disease phenotypes by
differences in its conformation and glycosylation. Such molecular analysis of prion strains suggests that new
variant Creutzfeldt–Jakob disease is caused by BSE exposure. The novel biology of prion propagation may not
be unique to these rare degenerative brain diseases.
INTRODUCTION acquired (Table 1). Inherited cases constitute ∼15% of cases,
acquired cases (kuru and iatrogenic CJD) are rare. Most human
The human prion diseases or transmissible spongiform cases are sporadic, and their precise aetiology is still unclear. Both
encephalopathies have been traditionally classified into human and animal prion diseases share common histopathological
Creutzfeldt–Jakob disease (CJD), Gerstmann–Sträussler–Scheinker features. The classical triad of spongiform vacuolation (affecting
disease (GSS) and kuru. They are rare neurodegenerative disorders any part of the cerebral grey matter), astrocytic proliferation and
affecting ∼1 person per million world-wide per annum. Despite their neuronal loss, may be accompanied by the deposition of amyloid
rarity, remarkable attention has been recently focused on these plaques (9). These plaques are composed principally of an
diseases. This is because of both their unique biology and concerns abnormal, partially protease resistant isoform of a host encoded
that the epidemic of a newly recognised bovine prion disease, bovine sialoglycoprotein, prion protein (PrP). PrP is expressed widely but
spongiform encephalopathy (BSE), could pose a threat to public at much higher levels in neuronal cells as a glycosylphosphatidyl
health through dietary exposure to infected tissues. inositol-anchored cell surface protein (10).
Transmissibility of the human diseases to experimental animals
was demonstrated with the transmission, by intracerebral MOLECULAR GENETICS OF THE HUMAN PRION
inoculation with brain homogenates into chimpanzees, of first kuru DISEASES AND A MODEL FOR PRION PROPAGATION
and then CJD in 1966 and 1968 respectively (1,2). Transmission
of GSS followed in 1981 (3). The prototypic prion disease, scrapie, The transmissible agent, or prion, seems to consist principally of
is a naturally occurring disease of sheep and goats, and has been an abnormal isoform of the prion protein (PrP), designated PrPSc
recognised for >200 years (4). Scrapie was demonstrated to be (11). PrPSc is known to be derived from the cellular isoform,
transmissible by inoculation in 1936 (5) and it was the recognition PrPC, by a post-translational mechanism (12,13) and evidence is
that histopathologically kuru, and then CJD, resembled scrapie that mounting that this change is conformational rather than covalent
led to suggestions that these diseases may also be transmitted by (14,15).While PrPC is fully sensitive to proteolysis, PrPSc, which
inoculation (6,7). Kuru is a neurodegenerative condition accumulates in the brain during disease, is partially protease
characterised principally by a progressive cerebellar ataxia which resistant. The human PrP gene (PRNP) is a single copy gene
reached epidemic proportions amongst the Fore linguistic group in located on the short arm of chromosome 20 (16); it spans 16 kb
the Eastern Highlands of Papua New Guinea and which was and contains two exons (17,18). The complete open reading
transmitted by cannibalism. Since the cessation of cannibalism in frame of 759 nucleotides is contained within the larger second
the 1950s the disease has declined but a few cases still occur as a exon which comprises the majority of the 2.4 kb mRNA. A key
result of the long incubation periods in this condition (8). advance in the understanding of prion biology was the identifica-
Transmission of CJD from case to case has occurred by a number tion of mutations in PRNP in the familial forms of the human
of routes involving accidental inoculation with human prions as a diseases. The first mutation to be identified in PRNP was in a
result of medical procedures. Such iatrogenic routes include the use family with CJD and constituted a 144 bp insertion into the coding
of inadequately sterilised neurosurgical instruments, dura mater sequence (19). A second mutation was reported in two families
and corneal grafting, and use of human cadaveric pituitary derived with GSS and genetic linkage was confirmed between this
growth hormone or gonadotrophin. missense variant at codon 102 and GSS, confirming that GSS was
The epidemiology of the human prion diseases encompasses the an autosomal dominant Mendelian disorder (20). This genetic
three aetiological types of prion disease: inherited, sporadic and variant was not present in the normal population but was rapidly
Tel: +44 171 594 3760; Fax: +44 171 706 7094; Email: j.collinge@ic.ac.uk1700 Human Molecular Genetics, 1997, Vol. 6, No. 10 Review
identified in numerous other unrelated GSS kindreds. These barrier’ is the degree of homology between the PrP in the donor
diseases are therefore both inherited in the germline and transmissi- and recipient species. Mice transgenic for hamster PrP lose their
ble by inoculation, and are biologically unique in this regard. species barrier to hamster prions (32). When such transgenic mice
The identification of one of the pathogenic PrP gene mutations were challenged with mouse derived prions, the infectivity they
in a case with neurodegenerative disease allows not only produced was fully pathogenic for mice but not hamsters, while
molecular diagnosis of an inherited prion disease (21) [and on challenge with hamster derived prions they produced prions
pre-symptomatic testing of at risk individuals (22)] but also its fully pathogenic to hamsters but not mice. The interpretation of
sub-classification according to mutation. Pathogenic mutations this finding is that a direct interaction between PrP molecules
reported to date in the human PrP gene consist of two groups: (i) occurs at some stage in the process of prion propagation and that
point mutations within coding sequence resulting in amino acid such interaction occurs most easily if the interacting PrP
substitutions in PrP or in one case production of a stop codon molecules are identical. Such work led to the idea that replication
resulting in expression of a truncated PrP; (ii) insertions encoding of prions may occur by PrPSc interacting directly with PrPC and
additional integral copies of an octapeptide repeat present in a catalysing the conversion of PrPC to PrPSc (32,33). Such an effect
tandem array of five copies in the normal protein (Fig. 1). The could then lead to a chain reaction of conversion leading to the
availability of direct gene markers for these diseases has enabled progressive conversion of increasing amounts of PrPC to PrPSc.
identification of highly atypical cases and has widened the known The pathogenic mutations in the prion protein may result in the
phenotypic range of these disorders (23,24). Remarkable production of a protein that converts spontaneously to PrPSc in
phenotypic variability may be present in the same family, with individuals with inherited prion diseases. Such a model provides
phenotypes ranging from classical CJD to atypical dementias an explanation of how a disease can be simultaneously inherited
with extremely long duration and lacking the typical histological and transmissible. The finding that nearly all sporadic CJD occurs
features of spongiform encephalopathy (25). Clinical and in homozygotes with respect to a common and apparently
pathological syndromes of the human inherited and other prion innocent protein polymorphism lends strong support to such a
diseases are reviewed in detail elsewhere (26). mechanism (28). Again prion protein interaction would occur
Genetic susceptibility is also relevant to both the sporadic and most favourably in individuals with two identical copies of the
acquired prion diseases. There is a common polymorphism of the prion protein. Heterozygotes, producing two different proteins,
human prion protein, with either methionine or valine present at would be somewhat protected, as if by an internal ‘species
residue 129. In Caucasians, ∼38% are homozygous for the more barrier’. It is possible that the occasional individuals hetero-
frequent methionine allele, 51% are heterozygotes and 11% are zygous at codon 129 who do develop sporadic CJD have a more
homozygous for valine (27). The large majority of sporadic CJD prolonged illness although more detailed studies are required to
occurs in individuals homozygous for this polymorphism (28) investigate this further (34). PrP valine 129 and PrP methionine
and most pituitary hormone related iatrogenic CJD cases are 129 would be expected to differ slightly in their propensity to
homozygotes, with a particular excess of valine homozygotes conversion to PrPSc. The excess of PrP valine 129 homozygotes
(29). This protective effect of PRNP heterozygosity is also seen amongst human pituitary hormone related cases suggests that PrP
in some inherited prion diseases where the age at onset of disease valine 129 may be the more susceptible (29).
is 1–2 decades later in heterozygotes at PRNP codon 129 as The aetiology of sporadic CJD remains unclear. It has been
compared with homozygotes (30,31). speculated that these cases might arise from somatic mutation of
Although prion diseases can be transmitted between PRNP or spontaneous conversion of PrPC to PrPSc as a rare
mammalian species by inoculation, in practice it is difficult to do stochastic event. The alternative hypothesis, that such cases arise
so, and typically transmission occurs in only a small proportion as a result of exposure to an environmental source of either human
of inoculated animals and then only after prolonged incubation or animal prions, is not supported by epidemiological evidence
periods on primary passage. On second and subsequent passage (35). Since transgenic mice expressing extremely high levels of
of infectivity into animals of the same species, incubation periods wild-type hamster or murine PrP develop a spontaneous
are typically much shortened, relatively synchronous as neuromuscular disease (36), that appears to be transmissible, it
compared with primary passage, and all inoculated animals has also been suggested that some cases of sporadic CJD may
succumb to disease. A key component of this so-called ‘species arise as a result of PrP overexpression.
Table 1. Human prion diseases
Type Clinical syndromes Aetiology
Acquired Kuru Cannibalism
Iatrogenic CJD Accidental innoculation with human prions
Sporadic CJD ?Somatic PRNP mutation
Atypical CJD or spontaneous conversion PrPC to PrPSc
Inherited Familial CJD Germline PRNP mutation
GSS
FFI
Various atypical dementias
CJD, Creuzfeldt–Jakob disease; GSS, Gerstmann–Sträussler–Scheinker disease; FFI, fatal familial insomnia; PRNP, human
prion protein gene.1701
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6, No.
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Figure 1. Pathogenic mutations reported to date in the human prion protein.
STRUCTURE AND FUNCTION OF PrP confirmed in a different PrP knockout line (43). However, others
have failed to replicate this finding, albeit using different
A high resolution structure of full length PrP has not yet been techniques and experimental conditions (44). That this phenotype
reported, but an NMR structure determination of a mouse PrP is rescued by expression of human PrP in such mice confirmed its
fragment spanning residues 121–231 represents an important step
specificity for PrP (45). These abnormalities of synaptic inhibition
forward (37). However, this structure lacks a highly conserved
are reminiscent of the neurophysiological abnormalities seen in
hydrophobic region (106–126), which contains several of the
patients with CJD and in scrapie infected mice (46), raising the
known pathogenic human mutations, as well as the N-terminal
octapeptide repeat region, expansion of which by integral possibility that prion neurodegeneration may be, at least in part,
numbers of repeat elements results in a group of inherited prion due to loss of PrP function rather than to a deleterious effect of
diseases. The conformation of this repeat region has been studied PrPSc (42). The relative normality of PrP null mice, which do not
by circular dichroism and appears to form an extended, flexible develop progressive neurodegeneration, could result from effective
domain with properties similar to the poly-L-proline type II helix adaptive changes during neurodevelopment. It is possible that the
(38). It has been hypothesised that this may form a low specificity sequestration of PrPC into PrPSc during prion disease in a
binding domain. developed nervous system lacking such plasticity has more severe
Despite the wealth of evidence indicating the central role of PrP consequences. Certainly, PrPSc does not appear to be toxic to cells
in these diseases, its normal cellular function remains unclear. Mice lacking PrPC (47) and PrPSc is difficult to detect in some cases of
homozygous for PrP null alleles appear to develop and behave the inherited human prion disease fatal familial insomnia (FFI)
normally (39). Such mice are completely resistant to developing (48), and in transgenic mice infected experimentally with FFI (49),
prion disease following inoculation and do not propagate suggesting that, at least in these cases, neurodegeneration may not
infectivity (40,41). However, electrophysiological studies have be the result of PrPSc toxicity. According to such a model, the gain
demonstrated impaired GABAA mediated synaptic inhibition in of function implied by the autosomal dominant mode of
hippocampal brain slices maintained in vitro and also reduced inheritance could reflect the formation of PrPSc which then
long-term potentiation (42), an abnormality independently functionally depletes PrPC by a dominant negative effect.1702 Human Molecular Genetics, 1997, Vol. 6, No. 10 Review
Two additional phenotypes have now been described in PrP mutations were found in PRNP coding sequence (60). Recently,
null mice, abnormalities of circadian rhythms (50) and cerebellar transmission of BSE to three macaques has been reported, with
Purkinje cell degeneration (51). Further neurophysiological production of histopathological appearances that are closely
abnormalities in the hippocampus of PrP null mice, including similar to the very unusual pattern of pathology seen in new
disrupted Ca2+-activated K+ currents and abnormal intrinsic variant CJD (61), providing further evidence that these cases may
properties of CA1 pyramidal cells have recently been reported result from BSE transmission. However, detailed comparisons
(52,53). with transmissions of typical CJD cases to macaques will be
needed to fully evaluate the significance of this finding.
If these cases do represent transmission of BSE to humans it is
CREUTZFELDT–JAKOB DISEASE AND THE ‘NEW
unclear why none had a pattern of unusual occupational or dietary
VARIANT’ PUTATIVELY LINKED TO BSE exposure to BSE; it is possible that they represent a genetically
Extensive epidemiological studies of CJD have been performed in susceptible sub-population. In addition, it is unknown why this age
a number of countries and all obtained broadly similar results (35). group should be particularly affected. However, little is known
The overall annual incidence in most studies was ∼1 case per about which foodstuffs contained high-titre bovine offal. It is
million. No significant case clustering is present other than with possible that certain foods containing particularly high titres were
respect to familial clusters. Cases are distributed apparently at eaten predominately by younger people. It is also possible that
random with a frequency related only to local population density. children have an inherently higher intrinsic susceptibility or shorter
In particular, there is no evidence for case-to-case spread or incubation period following dietary exposure to the BSE agent.
association with local scrapie prevalence. For instance, CJD is as Possibilities might include, for example, differences in gut
common in Australia and New Zealand, which have been scrapie permeability or lymphoreticular system or higher PrP expression
free for many years, as in the UK where scrapie is endemic. levels.
Numerous case control studies have not shown consistent Direct experimental evidence that new variant CJD may be
associations with particular occupational groups or dietary caused by BSE was provided by molecular analysis of human prion
components. strains (PrPSc typing) (see below). The identification of a
The core clinical syndrome of CJD is of a rapidly progressive biochemical marker that distinguished new variant CJD from
dementia usually with myoclonus. The onset is usually in the previously recognised forms of sporadic and iatrogenic CJD
45–75 year age group with peak onset between 60–65. Sporadic confirmed that this was a novel variant and implied that it was
CJD is exceedingly rare in individuals under age 30. The clinical caused by exposure to a single novel prion strain type (62). The
progression is typically over weeks progressing to akinetic mutism lack of any history of iatrogenic exposure to humans in these
and death often in 2–3 months. Around 70% of cases die in under patients suggested that this was a novel animal prion. The
6 months. molecular strain characteristics of new variant CJD closely
However, in late 1995 two cases of sporadic CJD were reported resembled those seen in BSE itself and BSE transmitted to mice,
in the UK in teenagers (54,55). Only four cases of sporadic CJD domestic cat and macaque, consistent with BSE being the origin of
had previously been recorded in the literature in teenagers, and new variant CJD (62). Such PrPSc markers are detectable in tonsil
none of these cases occurred in the UK. In addition, both cases (63), which may allow pre-mortem diagnosis of new variant CJD
were unusual in having kuru-type plaques, a finding seen in only without brain biopsy, and may potentially allow earlier diagnosis.
∼5% of CJD cases. Soon afterwards a third very young sporadic
CJD case occurred (56). These cases caused considerable concern
and the possibility was raised that they might suggest a link with TRANSMISSION STUDIES
BSE. By March 1996, further extremely young onset cases were
apparent and review of the histology of these cases showed a Experimental transmission studies of the human prion diseases
remarkably consistent and unique pattern (57). These cases were have, until recently, largely involved transmission to laboratory
named ‘new variant’ CJD although it was clear that they were also primates, in particular chimpanzees and squirrel monkeys. The
rather atypical in their clinical presentation; in fact most cases did extensive experience of the NIH group, reporting >300 successful
not meet the accepted clinical diagnostic criteria for probable CJD transmissions has recently been summarised (64). However,
(57) and, in some respects at least, clinically more closely transmission studies in primates are severely limited by the
resembled kuru (58). Extensive studies of archival cases of CJD expense of such studies and by ethical concerns as to the use of
or other prion diseases failed to show this picture and it seemed primates in such work. Attempts by most laboratories to transmit
that this did represent the arrival of a new form of prion disease human prions to rodents have been fairly unsuccessful, with only
in the UK. The statistical probability of such cases occurring by occasional transmissions occurring and then at very prolonged
chance was vanishingly small and ascertainment bias seemed incubation periods close to the natural lifespan of the mice. Some
most unlikely as an explanation. It was clear that a new risk factor groups have, however, reported more frequent transmissions
for CJD had emerged and appeared to be specific to the UK. The (65). Recently transgenic mice have become available which
UK Government advisory committee on spongiform have increased susceptibility to human prions. Mice expressing
encephalopathy (SEAC) concluded that, while there was no a chimaeric human/mouse PrP were susceptible to three CJD
direct evidence for a link with BSE, exposure to specified bovine isolates with short incubation periods (66). It has now become
offal (SBO) prior to the ban on its inclusion in human foodstuffs clear that transgenic mice expressing wild-type human PrP, but
in 1989, was the most likely explanation. A case of the new not mouse PrP, are highly susceptible to CJD, with all inoculated
variant was reported in France soon after (59). PRNP analysis mice succumbing at short incubation periods usually in the range
showed that all cases available for study were homozygous, for of 180–220 days (67,68). Such mice appear to lack a species
methionine at codon 129, and that no known or novel pathogenic barrier to human prions and can now be used for extensive studies1703
Human Molecular Genetics,
Nucleic Acids 1997,1994,
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22,10 Review
No. 1 1703
of the transmission characteristics of human prion diseases and to determinant of strain type with glycosylation being involved as
bioassay human prions (68). a secondary process. However, since it is known that different cell
types may glycosylate proteins differently, PrPSc glycosylation
patterns may provide a substrate for the neuropathological
MOLECULAR BASIS OF PRION STRAINS targeting that distinguishes different prion strains. Particular
A major problem for the ‘protein-only’ hypothesis of prion PrPSc glycoforms may replicate most favourably in neuronal
propagation has been how to explain the existence of multiple populations with a similar PrP glycoform expressed on the cell
isolates or strains of prions. Such strains are distinguished by their surface. Such targeting could also explain the different incubation
biological properties: they produce distinct incubation periods periods which also discriminate strains, targeting of more critical
and patterns of neuropathological targeting in inbred mouse lines. brain regions, or regions with higher levels of PrP expression,
As they can be serially propagated in inbred mice with the same producing shorter incubation periods.
Prn-p genotype they cannot be encoded by differences in PrP Such studies may allow a new molecular classification of
primary structure. Furthermore, strains can be re-isolated in mice human prion diseases; it is likely that additional PrPSc types or
after passage in intermediate species with different PrP primary strains will be identified. This may well open new avenues of
structures (69). Understanding how a protein-only infectious epidemiological investigation and offer insights into causes of
agent could encode such phenotypic information has been of ‘sporadic’ CJD. In addition, PrPSc typing can be applied to other
considerable biological interest. species; it is already apparent that PrP glycoform analysis alone
Support for the contention that strain specificity is encoded by can distinguish a number of mouse passaged scrapie strains (76).
PrP alone is provided by study of two distinct strains of The combination of fragment size and glycoform analysis should
transmissible mink encephalopathy prions which can be serially allow better resolution and might be applied, for instance, to study
propagated in hamsters, designated hyper (HY) and drowsy (DY) if BSE has transmitted to other species involved in the human diet
(70). These strains can be distinguished by differing such as sheep. It will be necessary to study the full range of sheep
physiochemical properties of the accumulated PrPSc in the brains strains to determine whether these can all be distinguished at a
of affected hamsters (71). Following limited proteolysis, strain molecular level from BSE, it is possible that more refined
specific migration patterns of PrPSc on polyacrylamide gels can molecular techniques may be necessary (77). Classical strain
be seen. DY PrPSc appears to be more protease sensitive than HY typing, involving mouse transmissions, takes 1–2 years and can
PrPSc producing a different banding pattern of PrPSc on Western only be applied to limited numbers of cases. Molecular strain
blots following proteinase K treatment. This relates to different typing takes days and allows large scale screening.
N-terminal ends of HY and DY PrPSc following protease The ability of a protein to encode a disease phenotype has
treatment and implies differing conformations of HY and DY important implications in biology, as it represents a non-
PrPSc (72). Furthermore, the demonstration that these strain Mendelian form of transmission. It would be surprising, and also
specific physiochemical properties can be maintained during in itself intriguing, if evolution had not used this mechanism for
vitro production of protease resistant PrP, when PrPC is mixed other proteins in a range of species. The recent identification of
with HY or DY hamster PrPSc, further supports the concept that prion-like mechanisms in yeast is particularly interesting in this
prion strains involve different PrP conformers (73). regard (78,79).
Recently, several human PrPSc types have been identified
which are associated with different phenotypes of CJD (62,74).
The different fragment sizes seen on Western blots following BOVINE TO HUMAN SPECIES BARRIER
treatment with proteinase K suggests that there are several
different human PrPSc conformations. However, to fulfil the As BSE appears to have transmitted to humans, a key issue is the
criteria of strains, these patterns must be transmissible to animals extent of the bovine to human species barrier. Clearly, this cannot
both in same and in different species. Remarkably, this is the case, be measured directly since this would require inoculation of
with both PrPSc fragment sizes and the ratios of the three PrP humans with BSE. However, transgenic models may offer a way
glycoforms (diglycosylated, monoglycosylated and unglyco- to address this issue, at least in part. The principal determinants
sylated PrP) maintained on passage in transgenic mice expressing of the ‘species barrier’ are the degree of homology between PrP
human PrP (62). Transmission of human prions and bovine prions molecules in the host and inoculum (32) and strain of agent;
to wild-type mice results in murine PrPSc with fragment sizes and however, BSE appears to be caused by a single prion strain (69).
glycoform ratios which correspond to the original inoculum (62). Transgenic mice expressing human PrP, which are competent to
New variant CJD is associated with PrPSc glycoform ratios which produce human PrPSc and ‘human’ prions on CJD challenge,
are distinct from those seen in classical CJD. Similar ratios are offer an opportunity to address the issue as to whether it is
seen in BSE and BSE when transmitted to several other species possible for bovine prions to induce production of human PrPSc.
(62). These data strongly support the ‘protein only’ hypothesis of To date results are reassuring. Incubation periods to BSE were
infectivity and suggest that strain variation is encoded by a unaltered in mice expressing human PrP in addition to mouse PrP,
combination of PrP conformation and glycosylation. and only mouse PrPSc appeared to be produced (68). A
Transmission of PrPSc fragment sizes from two different potentially more revealing experiment is to challenge mice
sub-types of inherited prion disease to transgenic mice expressing expressing only human PrP with BSE (68). No transmission
a chimaeric human mouse PrP has also been reported (75). As PrP occurred at incubation periods well beyond those of CJD in these
glycosylation is thought to be a co-translational process, the mice (80); it remains to be seen if transmission will occur at
different glycoform ratios may represent selection of particular longer incubation periods. These mice express valine at poly-
PrPC glycoforms by PrPSc of different conformations. According morphic codon 129 of PRNP and these studies are being repeated
to such a hypothesis, PrP conformation would be the primary with mice transgenic for human PrP methionine 129. This is of1704 Human Molecular Genetics, 1997, Vol. 6, No. 10 Review
particular importance given that all new variant CJD cases seen 20. Hsiao, K., Baker, H.F., Crow, T.J., Poulter, M., Owen, F., Terwilliger, J.D.,
to date are methionine 129 homozygotes. Westaway, D., Ott, J. and Prusiner, S.B. (1989) Linkage of a prion protein
missense variant to Gerstmann-Straussler syndrome. Nature 338, 342–345.
However, even the presence of a highly effective species barrier 21. Collinge, J., Harding, A.E., Owen, F., Poulter, M., Lofthouse, R., Boughey,
between cattle and humans does not exclude some degree of BSE A.M., Shah, T. and Crow, T.J. (1989) Diagnosis of Gerstmann–Straussler
transmission to humans, given the very large numbers of people syndrome in familial dementia with prion protein gene analysis. Lancet 2,
that have been exposed. Genetic susceptibility may well be 15–17.
important in this regard and in particular, PRNP codon 129 22. Collinge, J., Poulter, M., Davis, M.B., Baraitser, M., Owen, F., Crow, T.J. and
Harding, A.E. (1991) Presymptomatic detection or exclusion of prion protein
homozygotes would be expected to be at considerably higher risk gene defects in families with inherited prion diseases. Am. J. Hum. Genet. 49,
than heterozygotes, although it is possible that heterozygotes may 1351–1354.
simply have longer incubation periods. 23. Collinge, J., Owen, F., Poulter, M., Leach, M., Crow, T.J., Rossor, M.N.,
Hardy, J., Mullan, M.J., Janota, I. and Lantos, P.L. (1990) Prion dementia
without characteristic pathology. Lancet 336, 7–9.
24. Medori, R., Tritschler, H.J., LeBlanc, A., Villare, F., Manetto, V., Chen, H.Y.,
REFERENCES Xue, R., Leal, S., Montagna, P., Cortelli, P., Tinuper, P., Avoni, P., Mochi, M.,
Baruzzi, Q., Hauw, J.J., Ott, J., Lugaresi, E., Autilio-Gambetti, L. and
Gambetti, P. (1992) Fatal familial insomnia, a prion disease with a mutation at
1. Gajdusek, D.C., Gibbs, C.J.J. and Alpers, M.P. (1966) Experimental codon 178 of the prion protein gene. N. Engl. J. Med. 326, 444–449.
transmission of a kuru-like syndrome to chimpanzees. Nature 209, 794–796. 25. Collinge, J., Brown, J., Hardy, J., Mullan, M., Rossor, M.N., Baker, H., Crow,
2. Gibbs, C.J.J., Gajdusek, D.C., Asher, D.M., Alpers, M.P., Beck, E., Daniel, T.J., Lofthouse, R., Poulter, M., Ridley, R., Owen, F., Bennett, C., Dunn, G.,
P.M. and Matthews, W.B. (1968) Creutzfeldt–Jakob disease (spongiform Harding, A.E., Quinn, N., Doshi, B., Roberts, G.W., Honavar, M., Janota, I.
encephalopathy): transmission to the chimpanzee. Science 161, 388–389. and Lantos, P.L. (1992) Inherited prion disease with 144 base pair gene
3. Masters, C.L., Gajdusek, D.C. and Gibbs, C.J.J. (1981) Creutzfeldt–Jakob insertion: II: Clinical and pathological features. Brain 115, 687–710.
disease virus isolations from the Gerstmann-Straussler syndrome with an 26. Collinge, J. and Palmer, M.S. (1997) Human prion diseases. In Collinge, J.
analysis of the various forms of amyloid plaque deposition in the and Palmer, M.S., eds, Prion Diseases. Oxford University Press, Oxford,
virus-induced spongiform encephalopathies. Brain 104, 559–588. pp. 18–56.
4. McGowan, J.P. (1922) Scrapie in sheep. Scott. J. Agric. 5, 365–375. 27. Owen, F., Poulter, M., Collinge, J. and Crow, T.J. (1990) Codon 129 changes
5. Cuillé, J. and Chelle, P.L. (1936) La maladie dite tremblante du mouton in the prion protein gene in Caucasians. Am. J. Hum. Genet. 46, 1215–1216.
est-elle inocuable? C. R. Acad. Sci. 203, 1552–1554. 28. Palmer, M.S., Dryden, A.J., Hughes, J.T. and Collinge, J. (1991)
6. Klatzo, I., Gajdusek, D.C. and Zigas, V. (1959) Pathology of kuru. Lab. Homozygous prion protein genotype predisposes to sporadic Creutzfeldt–
Invest. 8, 799–847. Jakob disease. Nature 352, 340–342.
7. Hadlow, W.J. (1959) Scrapie and kuru. Lancet ii, 289–290. 29. Collinge, J., Palmer, M.S. and Dryden, A.J. (1991) Genetic predisposition to
8. Alpers, M.P. (1987) Epidemiology and clinical aspects of kuru. In S.B. iatrogenic Creutzfeldt–Jakob disease. Lancet 337, 1441–1442.
Prusiner and M.P. McKinley, eds, Prions: Novel infectious pathogens causing
30. Baker, H.F., Poulter, M., Crow, T.J., Frith, C.D., Lofthouse, R., Ridley, R.M.
scrapie and Creutzfeldt–Jakob disease. Academic Press, San Diego, pp.
and Collinge, J. (1991) Amino acid polymorphism in human prion protein
451–465.
and age at death in inherited prion disease. Lancet 337, 1286.
9. Beck, E. and Daniel, P.M. (1987) Neuropathology of transmissible spongi-
31. Dlouhy, S.R., Hsiao, K., Farlow, M.R., Foroud, T., Conneally, P.M., Johnson,
form encephalopathies. In S.B. Prusiner and M.P. McKinley, eds, Prions:
P., Prusiner, S.B. and Ghetti, B. (1992) Linkage of the Indiana kindred of
Novel infectious pathogens causing scrapie and Creutzfeldt–Jakob disease.
Gerstmann-Sträussler-Scheinker disease to the prion protein gene. Nature
Academic Press, San Diego, pp. 331–385.
Genetics 1, 64–67.
10. Baldwin, M.A., Stahl, N., Hecker, R., Pan, K., Burlingame, A.L., and
Prusiner, S.B. (1992) Glycosylinositol phospholipid anchors of prion 32. Prusiner, S.B., Scott, M., Foster, D., Pan, K.M., Groth, D., Mirenda, C.,
proteins. In S .B. Prusiner, J. Collinge, J. Powell and B. Anderton, eds, Prion Torchia, M., Yang, S.L., Serban, D., Carlson, G.A. and Raeber, A.J. (1990)
Diseases of Humans and Animals. Ellis Horwood, London. Transgenetic studies implicate interactions between homologous PrP
11. Prusiner, S.B. (1991) Molecular biology of prion diseases. Science 252, isoforms in scrapie prion replication. Cell 63, 673–686.
1515–1522. 33. Weissmann, C. (1991) Spongiform encephalopathies. The prion’s progress.
12. Borchelt, D.R., Scott, M., Taraboulos, A., Stahl, N. and Prusiner, S.B. (1990) Nature 349, 569–571, 1991.
Scrapie and cellular prion proteins differ in their kinetics of synthesis and 34. Collinge, J. and Palmer, M.S. (1991) CJD discrepancy. Nature 353, 802.
topology in cultured cells. J. Cell. Biol. 110, 743–752. 35. Brown, P., Cathala, F., Raubertas, R.F., Gajdusek, D.C. and Castaigne, P.
13. Caughey, B. and Raymond, G.J. (1991) The scrapie-associated form of PrP is (1987) The epidemiology of Creutzfeldt–Jakob disease: conclusion of a
made from a cell surface precursor that is both protease- and 15-year investigation in France and review of the world literature. Neurology
phospholipase-sensitive. J. Biol. Chem. 266, 18217–18223. 37, 895–904.
14. Gasset, M., Baldwin, M.A., Fletterick, R.J. and Prusiner, S.B. (1993) 36. Westaway, D., DeArmond, S.J., Cayetano-Canlas, J., Groth, D., Foster, D.,
Perturbation of the secondary structure of the scrapie prion protein under Yang, S., Torchia, M., Carlson, G.A. and Prusiner, S.B. (1994) Degeneration
conditions that alter infectivity. Proc. Natl. Acad. Sci. USA 90, 1–5. of skeletal muscle, peripheral nerves and the central nervous system in
15. Pan, K., Baldwin, M.A., Nguyen, J., Gasset, M., Serban, A., Groth, D., transgenic mice overexpressing wild-type prion proteins. Cell 76, 117–129.
Mehlhorn, I., Huang, Z., Fletterick, R.J., Cohen, F.E. and Prusiner, S.B. 37. Riek, R., Hornemann, S., Wider, G., Billeter, M., Glockshuber, R. and
(1993) Conversion of α-helices into β-sheets features in the formation of the Wuthrich, K. (1996) NMR structure of the mouse prion protein domain PrP
scrapie prion proteins. Proc. Natl. Acad. Sci. USA 90, 10962–10966. (121–231). Nature 382, 180–182.
16. Robakis, N.K., Devine Gage, E.A., Jenkins, E.C., Kascsak, R.J., Brown, 38. Smith, C.J., Drake, A.F., Banfield, A.B., Bloomberg, G.B., Palmer, M.S.,
W.T., Krawczun, M.S. and Silverman, W.P. (1986) Localization of a human Clarke, A.R. and Collinge, J. (1997) Conformational properties of the prion
gene homologous to the PrP gene on the p arm of chromosome 20 and octa-repeat and hydrophobic sequences. FEBS Lett. 405, 378–384.
detection of PrP-related antigens in normal human brain. Biochem. Biophys. 39. Bueler, H., Fischer, M., Lang, Y., Bluethmann, H., Lipp, H., DeArmond, S.J.,
Res. Commun. 140, 758–765. Prusiner, S.B., Aguet, M. and Weissmann, C. (1992) Normal development
17. Kretzschmar, H.A., Stowring, L.E., Westaway, D., Stubblebine, W.H., and behaviour of mice lacking the neuronal cell-surface PrP protein. Nature
Prusiner, S.B. and DeArmond, S.J. (1986) Molecular cloning of a human 356, 577–582.
prion protein cDNA. DNA 5, 315–324. 40. Bueler, H., Aguzzi, A., Sailer, A., Greiner, R.A., Autenried, P., Aguet, M. and
18. Oesch, B., Westaway, D., Walchli, M., McKinley, M.P., Kent, S.B., Weissmann, C. (1993) Mice devoid of PrP are resistant to scrapie. Cell 73,
Aebersold, R., Barry, R.A., Tempst, P., Teplow, D.B., Hood, L.E. and Raeber, 1339–1347.
A.J. (1985) A cellular gene encodes scrapie PrP 27–30 protein. Cell 40, 41. Sailer, A., Bueler, H., Fischer, M., Aguzzi, A. and Weissmann, C. (1994) No
735–746. propagation of prions in mice devoid of PrP. Cell 77, 967–968.
19. Owen, F., Poulter, M., Lofthouse, R., Collinge, J., Crow, T.J., Risby, D., 42. Collinge, J., Whittington, M.A., Sidle, K.C.L., Smith, C.J., Palmer, M.S.,
Baker, H.F., Ridley, R.M., Hsiao, K. and Prusiner, S.B. (1989) Insertion in Clarke, A.R. and Jefferys, J.G.R. (1994) Prion protein is necessary for normal
prion protein gene in familial Creutzfeldt–Jakob disease. Lancet 1, 51–52. synaptic function. Nature 370, 295–297.1705
Human Molecular Genetics,
Nucleic Acids 1997,1994,
Research, Vol. Vol.
6, No.
22,10 Review
No. 1 1705
43. Manson, J.C., Hope, J., Clarke, A.R., Johnston, A., Black, C. and MacLeod, 62. Collinge, J., Sidle, K.C.L., Meads, J., Ironside, J. and Hill, A.F. (1996)
N. (1995) PrP gene dosage and long term potentiation. Neurodegen. 4, Molecular analysis of prion strain variation and the aetiology of ‘new variant’
113–114. CJD. Nature 383, 685–690.
44. Lledo, P., Tremblay, P., DeArmond, S.J., Prusiner, S.B. and Nicoll, R.A. 63. Hill, A.F., Zeidler, M., Ironside, J. and Collinge, J. (1997) Diagnosis of new
(1996) Mice deficient for prion protein exhibit normal neuronal excitability variant Creutzfeldt–Jakob disease by tonsil biopsy. Lancet 349, 99–100.
and synaptic transmission in the hippocampus. Neurobiol. 93, 2403–2407. 64. Brown, P., Gibbs, C.J.J., Rodgers Johnson, P., Asher, D.M., Sulima, M.P.,
45. Whittington, M.A., Sidle, K.C.L., Gowland, I., Meads, J., Hill, A.F., Palmer, Bacote, A., Goldfarb, L.G. and Gajdusek, D.C. (1994) Human spongiform
M.S., Jefferys, J.G.R. and Collinge, J. (1995) Rescue of neurophysiological encephalopathy: the National Institutes of Health series of 300 cases of
phenotype seen in PrP null mice by transgene encoding human prion protein. experimentally transmitted disease. Ann. Neurol. 35, 513–529.
Nature Genet. 9, 197–201. 65. Tateishi, J., Koga, M. and Mori, R. (1981) Experimental transmission of
46. Jefferys, J.G.R., Empson, R.M., Whittington, M.A. and Prusiner, S.B. (1994) Creutzfeldt–Jakob disease. Acta Pathol. Jpn. 31, 943–951.
Scrapie infection of transgenic mice leads to network and intrinsic 66. Telling, G.C., Scott, M., Hsiao, K.K., Foster, D., Yang, S., Torchia, M., Sidle,
dysfunction of cortical and hippocampal neurons. Neurobiol. Disease 1, K.C.L., Collinge, J., DeArmond, S.J. and Prusiner, S.B. (1994) Transmission
3–15. of Creutzfeldt–Jakob disease from humans to transgenic mice expressing
47. Brandner, S., Isenmann, S., Raeber, A., Fischer, M., Sailer, A., Kobayashi, Y., chimeric human–mouse prion protein. Proc. Natl. Acad. Sci. USA 91,
Marino, S., Weissmann, C. and Aguzzi, A. (1996) Normal host prion protein 9936–9940.
necessary for scrapie-induced neurotoxicity. Nature 379, 339–343. 67. Telling, G.C., Scott, M., Mastrianni, J., Gabizon, R., Torchia, M., Cohen, F.E.,
48. Medori, R., Montagna, P., Tritschler, H.J., LeBlanc, A., Cortelli, P., Tinuper, DeArmond, S.J. and Prusiner, S.B. (1995) Prion propagation in mice
P., Lugaresi, E. and Gambetti, P. (1992) Fatal familial insomnia: A second expressing human and chimeric PrP transgenes implicates the interaction of
kindred with mutation of prion protein gene at codon 178. Neurology 42, cellular PrP with another protein. Cell 83, 79–90.
669–670. 68. Collinge, J., Palmer, M.S., Sidle, K.C.L., Hill, A.F., Gowland, I., Meads, J.,
49. Collinge, J., Palmer, M.S., Sidle, K.C.L., Gowland, I., Medori, R., Ironside, J. Asante, E., Bradley, R., Doey, L.J. and Lantos, P.L. (1995) Unaltered
and Lantos, P.L. (1995) Transmission of fatal familial insomnia to laboratory susceptibility to BSE in transgenic mice expressing human prion protein.
animals. Lancet 346, 569–570. Nature 378, 779–783.
50. Tobler, I., Gaus, S.E., Deboer, T., Achermann, P., Fischer, M., Rulicke, T., 69. Bruce, M., Chree, A., McConnell, I., Foster, J., Pearson, G. and Fraser, H.
Moser, M., Oesch, B., McBride, P.A. and Manson, J.C. (1996) Altered (1994) Transmission of bovine spongiform encephalopathy and scrapie to
circadian activity rhythms and sleep in mice devoid of prion protein. Nature mice: Strain variation and the species barrier. Philos. Trans. R. Soc. Lond.
380, 639–642. [Biol.] 343, 405–411.
51. Sakaguchi, S., Katamine, S., Nishida, N., Moriuchi, R., Shigematsu, K., 70. Marsh, R.F. and Kimberlin, R.H. (1975) Comparison of scrapie and
Sugimoto, T., Nakatani, A., Kataoka, Y., Houtani, T., Shirabe, S., Okada, H., transmissible mink encephalopathy in hamsters. II. Clinical signs, pathology,
Hasegawa, S., Miyamoto, T. and Noda, T. (1996) Loss of cerebellar Purkinje and pathogenesis. J. Infect. Dis. 131, 104–110.
cells in aged mice homozygous for a disrupted PrP gene. Nature 380, 71. Bessen, R.A. and Marsh, R.F. (1992) Biochemical and physical properties of
528–531. the prion protein from two strains of the transmissible mink encephalopathy
52. Colling, S.B., Collinge, J. and Jefferys, J.G.R. (1996) Hippocampal slices agent. J. Virol. 66, 2096–2101.
from prion protein null mice: disrupted CA2+-activated K+ currents. 72. Bessen, R.A. and Marsh, R.F. (1994) Distinct PrP properties suggest the
Neurosci. Letts 209, 49–52. molecular basis of strain variation in transmissible mink encephalopathy. J.
53. Colling, S.B., King, T.M., Collinge, J. and Jefferys, J.G.R. (1996) Prion Virol. 68, 7859–7868.
protein null mice: abnormal intrinsic properties of hippocampal CA1 73. Bessen, R.A., Kocisko, D.A., Raymond, G.J., Nandan, S., Lansbury, P.T., and
pyramidal cells. Brain Pathol. (abstract). Caughey, B. (1995) Non-genetic propagation of strain-specific properties of
54. Bateman, D., Hilton, D., Love, S., Zeidler, M., Beck, J. and Collinge, J. (1995) scrapie prion protein. Nature 375, 698–700.
Sporadic Creutzfeldt–Jakob disease in a 18-year-old in the UK. Lancet 346, 74. Parchi, P., Castellani, R., Capellari, S., Ghetti, B., Young, K., Chen, S.G.,
1155–1156. Farlow, M., Dickson, D.W., Sims, A.A.F., Trojanowski, J.Q., Petersen, R.B.,
55. Britton, T.C., Al-Sarraj, S., Shaw, C., Campbell, T. and Collinge, J. (1995) and Gambetti, P. (1996) Molecular basis of phenotypic variability in sporadic
Sporadic Creutzfeldt–Jakob disease in a 16-year-old in the UK. Lancet 346, Creutzfeldt-Jakob disease. Ann. Neurol. 39, 669–680.
1155. 75. Telling, G.C., Parchi, P., DeArmond, S.J., Cortelli, P., Montagna, P., Gabizon,
56. Tabrizi, S.J., Scaravilli, F., Howard, R.S., Collinge, J. and Rossor, M.N. R., Mastrianni, J., Lugaresi, E., Gambetti, P. and Prusiner, S.B. (1996)
(1996) Creutzfeldt–Jakob disease in a young woman. Report of a Meeting of Evidence for the conformation of the pathologic isoform of the prion protein
Physicians and Scientists, St. Thomas’ Hospital, London. Lancet 347, enciphering and propagating prion diversity. Science 274, 2079–2082.
945–948. 76. Somerville, R.A., Chong, A., Mulqueen, O.U., Birkett, C.R., Wood, S.C.E.R.
57. Will, R.G., Ironside, J.W., Zeidler, M., Cousens, S.N., Estibeiro, K., and Hope, J. (1997) Biochemical typing of scrapie strains. Nature 386, 564.
Alperovitch, A., Poser, S., Pocchiari, M., Hofman, A. and Smith, P.G. (1996) 77. Collinge, J., Hill, A.F., Sidle, K.C.L. and Ironside, J. (1997) Biochemical
A new variant of Creutzfeldt–Jakob disease in the UK. Lancet 347, 921–925. typing of scrapie strains. Nature 386, 564.
58. Collinge, J. and Rossor, M. (1996) A new variant of prion disease. Lancet 78. Wickner, R.B. (1994) [URE3] as an altered URE2 protein: Evidence for a
347, 916–917. prion analog in Saccharomyces cerevisiae. Science 264, 566–569.
59. Chazot, G., Broussolle, E., Lapras, C.I., Blattler, T., Aguzzi, A. and Kopp, N. 79. Ter Avanesyan, M.D., Dagkesamanskaya, A.R., Kushnirov, V.V. and
(1996) New variant of Creutzfeldt–Jakob disease in a 26-year-old French Smirnov, V.N. (1994) The SUP35 omnipotent suppressor gene is involved in
man. Lancet 347, 1181. the maintenance of the non-Mendelian determinant [psi+] in the yeast
60. Collinge, J., Beck, J., Campbell, T., Estibeiro, K. and Will, R.G. (1996) Prion Saccharomyces cerevisiae. Genetics 137, 671–676.
protein gene analysis in new variant cases of Creutzfeldt–Jakob disease. 80. Collinge, J. (1996) New diagnostic tests for prion diseases. N. Engl. J. Med.
Lancet 348, 56. 335, 963–965.
61. Lasmézas, C.I., Deslys, J.-P., Demaimay, R., Adjou, K.T., Lamoury, F.,
Dormont, D., Robain, O., Ironside, J. and Hauw, J.-J. (1996) BSE
transmission to macaques. Nature 381, 743–744.You can also read
