Prion diseases, or catching spongiform brain disorders, can be inheritable or catching. A common characteristic of prion disease involves the alteration of the prion protein (PrPc) to the isoform PrPsc (Hu et al., 2007). Prion extension involves a mechanism that changes PrPc to PrPsc in an autocatalytic manner (Harris and True, 2006).
PrPc is the normal prion protein, while PrPsc is the ‘scrapie’ isoform, which is the mutagenic prion protein and is considered an abnormal form. Prion diseases can occur in both humans and animals, although they are particularly rare in humans (Hu et al., 2002). They are known to be fatal neurodegenerative diseases (Hu et al., 2002).
Hu et al. (2002) explained that the reason for the increased interest in prion diseases in science and health is because they are biologically different in their characteristics compared to other known neurodegenerative diseases. There are many gaps in knowledge of prion diseases, such as the pathogenesis, what causes the mutagenic prion protein, and where prion diseases first arose from.
The PrPsc isoform, which is the most common characteristic of prion disease, is dominated by a beta sheet containing strong H bonds, and this structure is twisted. Many researchers have found that the strong H bonds make this isoform resistant to digestion protein kinase K, which means that this protein can build up particularly in the brain tissue, causing neural damage and possibly leading to prion diseases (Harris and True, 2006).
Hu et al. (2007) stated that because the PrPsc isoform is protein kinase K resistant, it is not broken down and therefore increasingly accumulates in the brain tissue of patients with prion diseases, causing further neurodegeneration.
Neurodegenerative diseases begin from the ground up and the incorrect conformational folding of a protein. The biological activity of a protein depends on its proper folding in the native conformation (Soto et al., 2002). Strong evidence has shown that protein misfolding plays a major role in catching spongiform encephalopathy pathogenesis (Soto et al., 2002).
There are many different types of prion diseases that have been found in both worlds and animate beings. One illustration includes Creutzfeldt-Jakob disease, and another illustration is Kuru (Hu et al., 2007). Examples of prion diseases concerned with animate beings include scrapie.
Bovine spongiform brain disorder is also an animal prion disease which is referred to as “mad cow disease” (Hu et al., 2002). Different forms of prion diseases, both human and animal, 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 form of human prion disease known as familial Creutzfeldt-Jakob Disease (Mikol, 1999). A common mutation at codon 178 had been found in the first instance.
Kuru is an acquired form of prion disease. This can be characterized by “kuru” plaques, which have been found in 70 percent of cases (Mikol, 1999). There has been recent interest in the kuru disease because of increased resistance to this disease. Kuru has the characteristic of rapidly devolving the central nervous system and is fatal (Goldfarb, 2002). There was an outbreak of kuru that killed many people in New Guinea, most of whom were from a small area populated by a culture known as the Bow people (Goldfarb, 2002).
It is not widely known how prion diseases first developed in worlds and animate beings, but it is thought that kuru became transmitted to humans via cannibalism (Goldfarb, 2002). It was a tradition in this culture to eat relatives who had died, resulting in “human-to-human transmission” (Mead et al., 2009).
By the late 1950s, there was a halt to cannibalism, and correlating with this, the number of people dying with kuru decreased. Additionally, no person after the 1950s had developed kuru (Goldfarb, 2002). However, how kuru first appeared in the Bow people is still unclear, but a conclusion has been made that the kuru epidemic must have started with a single individual who died from Creutzfeldt-Jakob disease and was then eaten through 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 vulnerability to Kuru (Goldfarb, 2002).
Goldfarb (2002) found that in the Bow culture, the 129 genotype methionine/methionine was the most common in patients enduring Kuru at an early age and that a change to methionine/valine showed that Kuru developed at a later age. Methionine/valine, valine/valine bearers survived the Kuru epidemic. Codon 129 heterogeneity is thought to be a resistance factor for Kuru disease (Mead et al., 2009).
Mead et al. also studied another polymorphism thought to be linked to kuru, the G127V polymorphism. They concluded that this G127V cistron is an agent gained that provides opposition to Kuru in a heterogeneous province and is not a mutant that could have caused the Kuru epidemic (Mead et al., 2009).
Many hypotheses have been developed in order to seek 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 that escapes protein kinase digestion and remains in brain tissue, causing neural 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 unnatural conformation” (Baskakov and Breydo, 2006). Strong evidence has shown that protein misfolding plays a major role in catching spongiform encephalopathy pathogenesis (Soto et al., 2002).
A number of hypotheses have been made to seek and explain the pathogenesis of prion diseases, all of which 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 ensuring that cells do not become damaged by oxidative stress (Westergard, 2007). The alteration 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 a 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, which is a reactive aldehyde that causes toxic stress in cells and, as a result, generates the production of free radicals.
Levels of MDA have been found at higher levels in scrapie-infected mice, showing 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 hence an abnormal form of this protein will allow oxidative stress, causing damage to neurons and ultimately leading to prion diseases (Westergard, 2007).
Evidence has also been found that the PrPc protein has SOD (superoxide dismutase) activity, and that the PrPc uses detoxification to remove any reactive oxygen species that could cause oxidative harm in cells. However, other studies have found evidence against this, so further work needs to be done to confirm this.
One way that the PrPc protein has been found to stop oxidative harm is “indirectly” by increasing the cell constituents, such as proteins. For example, a combination of copper-zinc SOD can remove and neutralize reactive oxidative species. Therefore, a mutated form of the prion protein would fail to do this, meaning that oxidative species remain in brain tissue, causing neural harm. However, Westergard et al. (2007) noted that these results had failed to become consistent in other scientific research.
Copper may also be involved in the pathogenesis of prion diseases. Copper is a substance necessary for the function of many enzymes. Abnormal metabolism in the body has been linked to many neurodegenerative diseases. It is thought that Cu 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, which suggests that there is a link to oxidative stress and neural harm, contributing to prion diseases.
The role of the immune system in the progression of prion diseases has been studied, and suggests that inflammatory processes, such as cytokines, play a part in causing neural harm in prion diseases. 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, such as the cell death model, which links necrosis and programmed cell death to the formation of prion diseases, are still unclear. Further research needs to be done to support this model.
In conclusion, many scientists have found that the PrPsc protein is the main cause of neural harm in patients. Mutations have been researched to identify the mutations linked to the disease. The pathogenesis of prion diseases is still unclear, as many hypotheses have been suggested. How prion diseases first arose is still unclear, and how they are transmitted is still being studied by scientists.
Mentions:
- Baskakov, I. V., & Breydo, L. (2007). Converting the prion protein: What makes the protein infective.
- 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., Choi, S., Choi, E. K., Carp, R., Kim, Y. S. (2002). The infectious mechanisms of prion disease. Elsevier Science.
- Hu, W., Kieseier, B., Frohman, E., Eagar, T. N., Rodger, N. R., Hartung, H. P., Stuve, O. (2007). Prion proteins: Physiological functions and roles in neurological disorders. Journal of Neurological Sciences.
- Mead, S., Whitfield, M. A., Poulter, M., Shah, P., Uphill, J., Campbell, T., Al-Dujaily, H., 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., Saborio, 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 characterization of the prion protein molecular types noticeable in the NIBSC Creutzfeldt-Jakob disease brain reference materials. Elsevier Science.
