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Pathology and biochemistry of prion disease varies with genotype in
Kate Soldan (email@example.com ),
Health Protection Agency Centre for Infections, Communicable Disease
Surveillance Centre, London, United Kingdom
The development of variant Creutzfeldt-Jakob disease (CJD) in transgenic
mice expressing the human PrP gene only occurred in those mice that were
methionine homozygotes at codon 129 of that gene, according to a
recently published study . Mice expressing valine at PrP 129
developed a different type of disease with different neuropathological
and molecular phenotypes and a different rate of secondary
Four distinct forms of the disease-related prion protein (PrPSc) have
been found in the brain tissue of patients with CJD: patients with
classical CJD have PrPSc types 1-3, and patients with vCJD have type 4
PrPSc [2,3,4]. Codon 129 of the human PrP gene encodes either methionine
or valine. This polymorphism appears to critically affect the
susceptibility of humans to prion diseases. All vCJD patients (i.e.
patients with type 4 PrPSc) tested to date have been homozygous for
methionine at codon 129.
In this study, mice strains with the human PrP gene instead of the mouse
PrP gene (transgenic mice) were given intracerebral inoculation with
brain tissue from vCJD patients and cows with bovine spongiform
encephalopathy (BSE). All the mice that were homozygous for methionine
at human PrP codon 129 developed clinical disease and neuropathological
signs typical of vCJD, as well as having type 4 PrPSc. Mice that were
homozygous for valine at human PrP codon 129 responded quite
differently: only 50% became infected and they developed type 5 PrPSc.
Type 5 was first described by the same research group in 1997 , also
in mice studies. Type 5 PrPSc has type 4-like glycoform ratios but gives
type 2-like digestion products after treatment with proteinase K, and is
associated with very weak diffuse PrP deposition in the brain in
contrast to the florid PrP plaques associated with type 4.
The study went on to investigate the within-species transmission of
these PrP types, i.e. transmission without a species barrier, and as
such, a model for human-to-human transmission of prion disease.
Within-species transmission of prion disease typically has a high (100%)
attack rate. Surprisingly, the brain inocula derived from four
clinically-affected mice that were homozygous for valine at human PrP
codon 129 failed to transmit clinical disease or asymptomatic prion
infection to other valine homozygous mice of the same breed.
Furthermore, when methionine homozygous mice were inoculated with brain
tissue containing type 5 PrPSc from the valine homozygous mice, some (10
of 13) developed sub-clinical infections with type 4 PrPSc and 3 of 13
developed clinical prion disease with type 2 PrPSc and a neuropathology
that resembled that of human sporadic CJD.
These findings indicate that codon 129 polymorphism determines the
ability of human PrP to form the various types of PrPSc, and also the
disease phenotype resulting from infection with BSE and vCJD prion.
Specifically, human PrP 129 valine appears not to be a compatible
substrate for the type of prion (type 4) seen in vCJD. The authors
recommend determination of PrPSc types amongst all human patients with
prion disease. This may further contribute to our understanding of
patterns of human prion disease in relation to exposure to BSE or
iatrogenic sources of vCJD, and also guard against missing BSE-related
infections that present as disease that resembles sporadic CJD more
closely than vCJD.
Based on these animal models, and therefore with caution, the authors
conclude that human infection with BSE-derived prions may not be
restricted to a single disease phenotype, but may result in sporadic
CJD-like or novel phenotypes in addition to vCJD, with the type of
disease experienced depending on the genotype of the host source of the
infection, and the genotype of the recipient.
1. Wadsworth JD, Asante EA, Desbruslais M, Linehan JM, Joiner S,
Gowland I, et al. Human Prion Protein with Valine 129 Prevents
Expression of Variant CJD Phenotype. Science 2004 Nov 11 [Epub
ahead of print].
2. Collinge J, Sidle KCL, Meads J, Ironside J, Hill AF. Molecular
analysis of prion strain variation and the aetiology of 'new
variant' CJD. Nature 1996; 383: 685-90 .
3. Wadsworth JD, Hill AF, Joiner S, Jackson GS, Clarke AR, Collinge
J. Strain-specific prion-protein conformation determined by metal
ions. Nature Cell Biol 1999; 1(1): 55-9.
4. Hill AF, Joiner S, Wadsworth JD, Sidle KC, Bell JE, Budka H et al.
Molecular classification of sporadic Creutzfeldt-Jakob disease.
Brain 2003; 126(Pt 6): 1333-46.
5. Hill AF, Desbruslais M, Joiner S, Sidle KCL, Gowland I, Collinge
J. The same prion stain causes vCJD and BSE. Nature 1997; 389:448-50.
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