Prion diseases or transmissible spongiform encephalopathy's can be inheritable or transmissible, a common feature of the prion disease involves the change of the prion protein (PrPc) to the isoform PrPsc (Hu et al, 2007). Prion propagation involves a mechanism that changes PrPc to PrPsc in an autocatalytic way (Harris and True, 2006). PrPc is said to be the normal prion protein and PrPsc the 'scrapie' isoform which is the mutagenic Prion protein said to be the un-normal form. Prion diseases can occur in both humans and animals, an though in humans they are particularly rare (Hur et al, 2002). They are known to be fatal neurodegenerative diseases (Hur et al, 2002). Hur et al (2002) said that the reason that there has become an increased interest in Prion diseases in science and health is because they are biologically different in their features compared with other known neurodegenerative diseases and that there are many gaps in the knowledge of prion diseases, for example the pathogenesis, what causes the mutagenic prion protein and where prion diseases first arose from . The PrPsc isoform which is known to be the most common feature of the prion disease is dominated by a beta sheet containing strong hydrogen bonds and this structure is twisted, many researchers have found that the strong hydrogen bonds make this isoform resistant to digestion protein kinase k meaning that this protein can build up particularly in the brain tissue causing neuronal damage and therefore possibly leading to prion diseases. (Harris and true, 2006). Hu et al (2007) said that because the PrPsc isoform is protein kinase k resistant it isn't broken down and therefore increasingly accumulates in the brain tissue of patients with prion diseases and causes further neurodegeneration.
Neurodegenerative diseases commence from the build up and the wrong conformational folding of a protein, the biological activity of a protein depends on its correct folding in the native conformation (Soto et al, 2002). Strong evidence has been shown that protein misfolding plays a major role in transmissible spongiform encephalopathy pathogenesis (Soto et al, 2002).
There are many different types of prion diseases that have been found in both humans and animals one example includes Creutzfeldt-Jakob disease and another example is Kuru (Hu et al, 2007). Examples of prion diseases concerned with animals include scrapie. Bovine spongiform encephalopathy is also an animal prion disease which is also referred to as 'mad cow disease' (Hu et al, 2002). Different forms of prion diseases both human and animal forms are associated with different forms of PrPsc (Soto et al, 2002). Many mutations in the PrPsc protein in prion disease have been found and linked to the different forms of Prion disease. The polymorphism at codon 129 has been found to play a major role in the phenotypic expression of Creutzfeldt-Jakob disease which is the most frequent type of Prion disease (Mikol, 1999). Mutations and insertions have been found to be involved in another from of human prion disease known as familial Creutzfeldt-Jakob Disease (Mikol 1999). A common mutation at codon 178 had been found in the first case. Kuru is an acquired from of the prion disease, this can be characterised by 'kuru' plaques which have been found in seventy percent of cases (Mikol, 1999). There has become recent interest in the kuru disease because of an increased resistance to this diseases. Kuru has the characteristic of quickly degenerating the central nervous system and it is fatal (Goldfarb, 2002). There was an outbreak of kuru which killed many people in new guinea most of these people were from a small area populated by a culture known as fore people (Goldfarb, 2002). It is not widely known how Prion diseases first developed in humans and animals but it is thought that kuru became transmitted to humans via cannibalism (Goldfarb, 2002). It was pursued in this culture to eat relatives who had died , therefore resulting in 'human to human transmission' (Mead et al, 2009). By the late 1950's there was a stop to cannibalism and correlating with this the umber of people dying with kuru decreased also no person after the `1950,s had developed Kuru (Goldfarb, 2002). However how kuru first appeared in the fore people is still unclear, but a conclusion has been made that the kuru epidemic must have started with a single person who died from Creutzfeldt-Jakob disease and then was eaten by traditional cannibalism . Many studies have aimed to find the mutations involved in Kuru. The methionine/valine variation encoded by the 129 codon in the PRNP gene has been recorded in many Kuru patients, a recent study has shown that the 129 genotype is associated with an increased vunerability to Kuru (Goldfarb, 2002). Goldfarb 2002 found that in the fore culture the 129 genotype methionine/methionine was the most common in patients suffering from Kuru at an early age and that a change to methionine/valine showed that Kuru developed at a later age. Methionine/valine, valine/valine carriers survived the Kuru epidemic, codon 129 heterogeneity is thought to therefore be a resistance factor for Kuru disease (Mead et al, 2009). Mead et al also studied another polymorphism which was thought to be linked to kuru, the G127V polymorphism. They concluded that this G127V gene is an agent gained that provides resistance to Kuru in a heterogeneous state and isn't a mutation which could have caused the Kuru epidemic (Mead et al, 2009).
Many hypothesise have been developed in order to try and explain prion diseases, however none have been fully accepted.
The most common hypothesis is the Prion hypothesis which suggests that the agent causing neurodegeneration is the prion protein but the mutagenic form which escapes protein kinas k digestion and remains in brain tissue causing neuronal damage (Yull et al, 2008)."The Prion hypothesis states that the infectious agent of prion diseases is an abnormally folded isoform of the prion protein (PrPsc) that replicates its abnormal conformation" (Baskakov and Breydo, 2006). Strong evidence has been shown that protein misfolding has a major role in transmissible spongiform encephalopathy pathogenesis (Soto et al, 2002).
A number of hypotheses have been made in order to try and explain the pathogenesis of prion diseases, they all correlate to the prion protein hypothesis indicating that the mutated prion protein PrPsc is involved in the pathogenesis.
One hypothesis links the pathogenesis to oxidative stress and suggests that PrPc is involved in making sure that cells don't become damaged by oxidative stress (Westergard, 2007). The change in the function of PrPc for example by a mutation/ misfolding may therefore be linked to the role in disease (Westergard, 2007). Oxidants are produced as the result of another action in respiration usually via abnormal anaerobic respiration in many people with neurodegenerative diseases (Hur et al, 2002). Levels of MDA can indicate oxidative stress, this is a reactive aldehyde which causes toxic stress in cells and as a result generates the production of free radicals, levels, levels of MDA have been found a higher levels in scrapie infected mice showing an involvement of oxidative stress (Hur et al, 2002).. It has therefore been suggested that the normal prion protein PrPc protects cells from oxidative stress and therefore an abnormal form of this protein will allow oxidative stress and therefore cause damage to neurones and therefore leading to prion diseases (Westergard, 2007).
Evidence has also been found that the PrPc protein has SOD (Superoxide dimutase) activity and that the PrPc uses detoxification to remove any reactive oxygen species that could cause oxidative damage in cells, however other studies have found evidence against this therefore further work needs to be done to confirm this. One way that the PrPc protein has been found to stop oxidative damage is 'indirectly' by increasing the cell components such as proteins, for example a combination of copper-zinc SOD that can remove and damage and circulating reactive oxidative species, therefore a mutated from of the prion protein would ail to do this meaning that oxidative species remain in brain tissue causing neuronal damage (Westergard et al, 2007). However Westergard et al (2007) said that these results had failed to become repetitive in other scientific research.
Copper may also be involved in the pathogenesis of prion diseases. Copper is a substance necessary to the function of many enzymes (Westergard et al, 2007). Abnormal metabolisms in the body have been linked with many neurodegenerative diseases, it is thought that copper ions can change the properties of the normal prion protein (Westergard, 2007). Hur et al (2002) have reported that iron is involved in neurodegenerative diseases, scientists have shown that the amount of fe3+ is much higher in the brains of scrapie infected people, fe3+ is needed for free radical formation , concluding that there is a link to oxidative stress and neuronal damage therefore contributing to prion diseases (Hur et al, 2002).
A role of the immune system in the propagation of prion diseases ahs been studied and suggests that inflammatory processors for example cytokines play a part in causing neuronal damage in prion diseases (Hur et al, 2002). The role of PrPc and the immune system still remains unknown(Hur et al, 2002). Although many hypotheses have been suggested many are still unclear. Other models for example the cells death model which links necrosis and apoptosis to the formation of a prion disease are still unclear further research needs to be done to support this model.
To conclude many scientist's have found that the PrPsc protein is the main cause of neuronal damage in patients. Mutations have been researched to find out the mutations linked to the disease. It is unclear of the pathogenesis of prion diseases as many hypotheses have been suggested. How prion diseases first arose is still unclear and how they are transmitted is still undergoing scientific research.
- Baskakov I.V, Breydo L, 2007, Converting the prion protein: what makes the protein infectious.
- Cohen.F.E, 1999, Protein Misfolding and prion disease, Academic press.
- Goldfarb.L.G, 2002, Kuru; the old epidemic in a new mirror, Elsevier.
- Harris.D.A, True.H.L, 2006, New insights into prion structure and toxicity, Elsevier inc.
- Hur.K, Kim.J, Choir.S, Choir.E.K, Carp.R, Kim.Y.S, 2002, The pathogenic mechanisms of prion disease, Elsevier science.
- Hu.W, Kieseir.B, Frohman.E, Eagar.T.N, Rodger.N.R, Hartung.H.P, Stuve, 2007, Prion proteins: Physiological functions and role in neurological disorders, journal of neurological sciences.
- Mead.S, Whitfield.M.A, Poulter.M, Shah.P, Uphill J, Campbell, Al-Dujaily, Hummerich.H, Beck.J, Mein.C.A, Verzilli.C, Whittaker.J, Alpers.M.P, Collinge.J, 2009, A Novel Protective Prion Protein Variant that Colocalizes with Kuru Exposure, Massachusetts Medical Society.
- Mikol.J., 1999, Neuropathology of prion diseases, Elsevier science.
- Soto.C, Sabotio.G.P, Anderes.L, 2002, Cyclic amplification of protein misfolding: application to prion related disorders and beyond, Elsevier science.
- Westergard.L, Christensen H.M, Harris D.A, 2007, The cellular prion protein (PrPc):Its physiological function in disease, Elsevier.
- Yull.H.M, Ironside J.W, Head.M.W, 2009, Further characterisation of the prion protein molecular types detectable in the NIBSC Creutzfeldt-Jakob disease brain reference materials, Elsevier science.