Variant Creuzfeldt-Jacob disease

Discuss the histopathological and molecular evidence implicating prion protein (PrP) in the pathogenesis of variant Creuzfeldt-Jacob disease (vCJD)

Variant Creutzfeldt-Jacob disease (vCJD) is a non-familial form of CJD, within the family of transmissible spongiform encephalopathies (TSEs).  TSEs, as the name suggests, are all highly transmissible - with infection of Central Nervous System (CNS) tissues highest (Knight 2003).  
vCJD was first observed clinically in 1994 and termed variant CJD by Will et al in 1996 due to the differences it presented to the more traditional forms of CJD such as sporadic CJD (sCJD). 

Prions were first characterised by Prusiner in his seminal paper of 1982.  The name prion is derived from the terms proteinaceous and infectious, used to differentiate prions from normal transmissible agents such as viruses (Prusiner 1982). Initially tentative linkage between CJD and prions has now become relatively widespread as molecular and histopathological evidence is provided.  

The clinical features of vCJD

Patients with vCJD have a drastically lower age of death (28 years) compared to those with sCJD (67 years) (CJD Referral unit 2005).  Following the initial 10 cases in 1996, numbers have risen to 25 in 1998 (Prusiner 1998), and 153 confirmed deaths to December 2004 (CJD Referral Unit 2005).
vCJD is characterised by a large degree of psychiatric involvement along with painful sensory symptoms (Knight and Will 2004).  In the majority of cases there are around 6 months of psychiatric and behavioural symptoms prior to the onset of neurological symptoms.

The causes of vCJD

vCJD shares many similarities with bovine spongiform encephalopathy (BSE).  It is widely believed that vCJD is actually caused via ingestion of BSE infected bovine material, especially as the vast majority of the cases are found in the UK, correlated with the incidence of BSE. Experimentally induced BSE models share a similar isotype of deposited protein as vCJD (Will 2002).
However the method by which the causative agent is transmitted to, or acts upon, the human is not known.  There are a number of theories, but the accepted ones take the role of prion proteins for granted, just differing on the method by which they actually infect CNS cells.
Prion proteins  

It is known that prion proteins are infectious and easily transmissible pathogens that are formed via modification of the mammalian cellular prion protein (PrPC) (Prusiner 1998).  PrPC is a cell surface glycoprotein (Ironside 1998); the normal cellular function of which is unclear.  However, it has been suggested that it may relate to adhesion, signal transduction, or copper metabolism (Hur et al 2002).  PrPC is a 253 amino acid protein, which has a short half-life in man and contains no nucleic acid.  PrPC is encoded by the PRNP gene on chromosome 20 (Knight 2004).

The ordinary structure of PrPC involves -helices and a coiled structure, which is changed via post-translational modifications (Prusiner 1998) to a -sheet structure on conversion to PrPSc (Poser 2002). It is these -sheets that give rise to the insoluble nature of PrPSc and their resistance to denaturation, degradation (Ironside 1998) and sterilisation (Collinge 1999).  

Whilst vCJD is not a genetic disease all confirmed cases thus far have been found to be homozygous for the 129 MM (methionine) codon 129 of the PRNP gene (Knight 2004).  This is not actually a mutation, as it is a naturally occurring polymorphism (DeArmond and Bouzamondo 2002), found in 40% of the UK population (Knight 2004).  However 129MM is a predisposing factor for vCJD and it has been suggested that heterozygosity for codon 129 might actually be protective against inherited prion diseases (Collinge 1999).

Prion proteins in vCJD

In addition to the gliosis, vacuolation, astrocytosis and generalised neuronal loss characteristic of vCJD, PrPSc is consistently present in areas of pathology.  
Figure 1 shows the different appearance of vCJD and sCJD (DeArmond and Bouzamondo 2002).  Vacuolar degeneration is visible in both but there are little or no PrP plaques in sCJD, whereas they are numerous in vCJD. Indeed the two varieties of CJD are often characterised partially in terms of neuronal plaques, in that 100% of vCJD plaques contain PrP, whereas <15% of plaques in sCJD contain PrP (Ironside 1998).
Figure 1. The pathological changes in the cortex of vCJD (left) and sporadic CJD (right)(DeArmond and Bouzamondo 2002)

It is the accumulation of PrPSc in the CNS that causes the neuronal loss and astrocytosis associated with prion diseases (Hur et al 2002).  Indeed astrocyte proliferation and infection with PrPSc can actually be detected before neuronal infection in many animal models of vCJD (Brown et al 2003). The exact mechanism by which this occurs is not known but it has been suggested that oxidative stress, mitochondrial dysfunction and disrupted iron metabolism may all have a role (Hur et al 2002).  Neuronal death could then arise via apoptosis - programmed cell death as a result of perceived non-viable cells; or necrosis, whereby cells were actually degraded.

The prion transmission hypotheses

The protein only hypothesis of the TSE is that an abnormal form of a normal host protein catalyses the malformation of itself, leading to a non viable cellular form.  By contrast the virus theory suggests that there is a specific viral agent that transmits the disease from one animal to another, and the pathology is the result of the disease state (Caughey and Chesebro 1997).
The nucleation theory states that a seed PrPSc molecule gives rise to a cascadal conversion of PrPC to further PrPSc (Poser 2002).  
With all these hypotheses it is the prion proteins are solely responsible for the development of the disease state.  


It seems difficult to refute the role of prions in vCJD when they are so widespread in the observable pathology. There are alternative theories put forward from time to time, relating to cellular events such as calcium and copper metabolism, and oxidative stress, but these rarely garner much support.  It is true that these all occur but it is generally accepted that they are closely linked to the deposition of PrPSc.  Of course it is not known whether the protein deposition is the cause or effect of these disrupted cellular processes but to a certain extent this does not matter.  What is important is that PrPSc is present in vCJD, so efforts need to be made to discover ways of removing this protein, or catalysing it’s conversion back to the harmless PrPC form.  

Brown, D. A.; Bruce M. E.; and Fraser J. R. 2003 Comparison of the neuropathological characteristics of bovine spongiform encephalopathy (BSE) and variant Creutzfeldt-Jakob disease (vCJD) in mice Neuropathology and Applied Neurobiology, 29, 262-272

Caughey, B. and Chesebro, B. 1997, Prion protein and the transmissible spongiform encephalopathies, Trends in Cell Biology, 7(2), 43-84

Collinge J. 1999. Variant Creutzfeldt-Jakob disease. Lancet, 354(9175),317-323

DeArmond, S. J. and Bouzamondo, E. 2002. Fundamentals of prion biology and diseases.  Toxicology, 181-182, 9-16

Hur K, Kim JI, Choi SI, Choi EK, Carp RI, Kim YS. 2002 The pathogenic mechanisms of prion diseases. Mechanisms of Ageing and Development.123(12),1637-47.

Ironside JW. 1998. Prion diseases in man. Journal of Pathology. 186, 227-34

Knight, R. 2003. Variant CJD: the present position and future possibilities International Journal of Pediatric Otorhinolaryngology, 67 (S1), S81-S84

Knight, R. 2004. Prion Diseases. Vox Sang: 87(1),S104-S106.

Knight, R. S. G. and Will, R. G. 2004 Prion diseases Journal of Neurology Neurosurgery and Psychiatry. 75. 36-42

The National Creutzfeldt-Jakob Disease Surveillance Unit. 2005. available online at

Poser, C.M. 2002. Notes on the history of the prion diseases. Part II. Clinical Neurology and Neurosurgery, 104 (2),77-86

Prusiner, S. B. 1982. Novel proteinaceous infectious particles cause scrapie.
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Prusiner, S. B. 1998, Prions Proceedings of the National Academy of the Sciences of the USA 95,13363-13383,
Ritchie DL, Head MW, Ironside JW. 2004. Advances in the detection of prion protein in peripheral tissues of variant Creutzfeldt-Jakob disease patients using paraffin-embedded tissue blotting. Neuropathology and Applied Neurobiology; 30(4), 360-368.

Will, R. G.; Ironside, J. W.; Zeidler, M.; Estibeiro, K.; Cousens, S. N.; Smith, P. G.; Alperovitch, A.; Poser, S.; Pocchiari M.; and Hofman, A. 1996.  A new variant of Creutzfeldt-Jakob disease in the UK. Lancet 347(9006),921-925.

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