Prion dieases (PrD), are fatal neurodegenerative diseases found in humans and different animal species. Prions are the infectious agents of these diseases and consist of large protein aggregates of the prion protein, PrPSC (Scheckel & Aguzzi, 2018). While first recognized as scrapie in sheep, Creuztfeldt-Jakob (CJD) was first described by two scientists of the same name in the 1920. Hans Gerhard Creutzfeldt and Alfons Maria Jakob were two neurologists perplexed by this neurological disease with an unknown cause. Initially thought to be a virus, prions were not identified as being proteins until the 60s, when several scientists proposed that scrapie, CJD and kuru were of proteinaceous origin (Zabel & Reid, 2015).
Stanley Prusiner coined the term “prion” in 1982, along with suggesting that CJD was of the same origin (Prusiner, 1982). This coinage earned him a Nobel Prize in Medicine in 1997. In 1985, the Prisiner team was able to isolate the gene that codes for the non-infectious prion protein, PrPC (Oesch et al., 1985). Further research showed the necessity of PrPC in the body for PrPSC infection after inoculation with PrPSC prions (Büeler, et al., 1993). Characterization of the different prion diseases required a greater understanding of the PrPSC and PrPC proteins, and how they are different.
There are three different types of Creutzfeldt-Jakob disease: genetic/familial/inherited, sporadic, and acquired. There are two types of acquired CJD, variant (contracted from eating meat that is infected with bovine spongiform encephalopathy, BSE) and iatrogenic (contracted from medical procedures). Genetic CJD is caused by a mutation in the prion protein gene, PRNP. Sporadic CJD has an unknown etiology— cases seem to be entirely random and no causational or correlational links have been found. Both of these are late onset and lead to death within a year of disorder development. It is important to note that in a study of familial CJD cases, the majority of cases pointed at CJD being autosomal dominant, leading to earlier disease onset. That being said, the study is from 1981 (Masters, Gajdusek, & Gibbs, 1981). Acquired CJD is a different matter – due to it being acquired, a large range of ages can acquire it. Individuals from 17-95 years of age have been diagnosed with acquired CJD. Acquired CJD tends to have a longer incubation period, the average being 17 years (Holman et al., 2010). These statistics, however, have the potential to be biased due to the a level of underreporting. The characteristics and symptoms of CJD make it hard to distinguish from a variety of other neurodegenerative disease, and it is possible that many cases go undiagnosed and unnoticed (Scheckel & Aguzzi, 2018). Acquired CJD is therefore reliant on a horizontal transmission, making it scarier and more of a public health concern than sporadic and familial.
Figure 1. This is an image of the prion protein. Most of the mutations associated with genetic CJD are found in the blue -Helix region of the protein.
Medical Diagnosis and Disease Description
Creutzfeldt-Jakob is incredibly hard to diagnose ante-mortem. A diagnosis requires the confirmation of the presence of protease-resistant prion deposits, which necessitates a brain biopsy. Currently, the best method of diagnosis is based on symptoms expressed and the exclusion of other neurodegenerative diseases. This can be supported through a variety of different tests. Magnetic resonance imaging (MRI) results are often abnormal,
electroencephalography (EEG) results have periodic sharp waves, characteristic of CJD, and the detection of elevated levels of 14-3-3 protein in cerebrospinal fluid (Belay, et al., 2005; Zanusso, et al., 2016). However, even the usage of these tests has proven to be difficult, as they are indicative of neuronal damage, not PrD (Scheckel & Aguzzi, 2018).
The three different varieties of CJD are all characterized by spongiform degeneration, astrocyte gliosis, and amyloid aggregates in the brain (Johnston & Conly, 2001). Early stage CJD typically presents itself as dementia, loss of muscle coordination, changes in personality, and impaired memory and judgement. Progression of CJD leads to blindness, myoclonus, paralysis, coma, and eventual death (Prusiner, 1998; Johnston & Conly, 2001). Clinically, iatrogenic CJD differs in that cases of it have shown cerebellar presentations in those who had received pituitary hormone grafts (Brown et al., 2000). This by itself, however, is not enough to determine the variety of CJD to be acquired and not sporadic. Iatrogenic CJD also differs in that the initial presenting symptoms tend to be more psychological and sensory, and are then followed by a slew of neurological symptoms (Collinge, 1999).
Control Strategies and Treatment
Acquired Creutzfeldt-Jakob disease, variant and iatrogenic, are highly infectious and this level of infectivity requires a strict and controlled biosafety protocol. Variant CJD (vCJD) is acquired through the consumption of the animal form of this disease, bovine spongiform encephalopathy (BSE, commonly known as mad cow disease). The introduction of CJD into the mainstream media was through a spread of vCJD through food consumption in the UK in the 1990s. Infected meat was introduced into the food supply and led to the subsequent death of nearly 100 known individuals (Hilton, 2000). Prevention and control strategies include proper screening of sick cattle, quarantining, and culling of those infecting. An estimated 400,000 infected cattle entered the food supply, a situation that could have been avoided with proper screening and proper care. The spread of vCJD is almost parallel to how Kuru was spread in Papua New Guinea, before cannibalistic practices were halted (Zigas, 1970). There have also been efforts to selectively breed sheep to have more resistant PrP genotypes to lower transmission rates. This has potential to be reproduced in other animals used in food production, like cows and goats, if and when PrP isolates are determined to be more resistant genotypes to mutation (Priem et al., 2014).
Iatrogenic CJD (iCJD) is acquired through medical procedures. This typically involves usage of contaminated equipment in medical procedures, allowing the prion to enter the body, blood transfusions, and a variety of other ways. There are protocols in place to assist hospitals in dealing with contaminated surgical equipment, to avoid spread and infection of other patients. A contamination is incredibly hard to get under control and to eliminate. Prions have a high resistance and tolerance to proteases, heat and decontamination methods; effective methods of decontamination include incineration, steam sterilization at 132C for 18minutes, or immersion in 12.5% NaOh for 30 minutes (Steelman, 1999)
Treatment for CJD is nonexistent, and center more around palliative care (Centers for Disease Control, 2018). Many drugs and routes of treatment have been attempted, including but not limited to quinacrine, pentosane polysulfate, immunotherapies, and even the use of lentiviruses, but none of these routes have produced results (Skinner et al., 2015). Interestingly enough, pomegranate seed oil nano-emulsions have been shown to have preventative treatment for neurodegenerative diseases, working to prevent great neuronal loss (Mizrahi et al., 2014). A study with great promise involved using heterologous prion proteins as a treatment for individuals with prion diseases. This would mean using normal prion proteins, PrPC, from one species as a treatment in a different species (Skinner et al., 2015).
Evolution and Virulence
The mechanism by which the infectious prion protein is able to proliferate throughout the central nervous system is called nucleation and fragmentation. PrPSC will come into contact with a PrPC protein, touch it, and transform it to the mutant PrPSC. This allows for the formation of large aggregates or PrPSC that will break into pieces, to be able to divide and conquer (Scheckel & Aguzzi, 2018).
Although much of the research in transmission between organisms and virulence of PrDs has been in bovine spongiform encephalopathy, there is a high level of translatability to the human forms. Variant CJD is a perfect example of a PrPSC crossing-over event; the transmission of bovine spongiform encephalopathy to humans through meat consumption. Other than this event, studies have had conflicting reports on other forms of transmission. Sheep scrapie was shown to be able to infect goats (Pattison, et al., 1959), but not cattle (Robinson et al., 1995). The variety in results can be due to the highly variable incubation period of PrDs. In mice, incubation periods ranged from 60 days to over 700 days (Igel-Egalon, et al., 2018). In situations where crossing-over events were successfully induced, strains were shown to be different, suggesting that the PrPSC has to undergo some sort of evolutionary change to be able to inhabit and infect the new species (Bartz, et al., 2000). This led to the belief that the ability to transmit a PrD is dependent on the host’s PrPC protein structure, (Igel-Egalon, et al., 2018). BSE has been shown to be easily transmitted to different animal species, but the reason is still unknown.
Polymorphisms in the PrP gene have been shown to have large implications for the transmissibility of a prion strain, as well as susceptibility of the host. A single point mutation is responsible for familial or inherited CJD. An amino acid change in PrPC, leading to homozygosity for methionine or valine at position 129 has been shown to lead to increased sensitivity to PrD, and a homozygosity for methionine at this position has been seen in nearly every case of vCJD to date (Palmer, et al., 1991; Zeidler et al., 1997). In sheep, over 55 different PrP polymorphisms have been isolated, the most important being a mutation of alanine to valine at codon 136. This mutation leads to high disease susceptibility and fast death upon infection. Inversely, a glutamine to arginine mutation at codon 171 leads to near resistance to PrD (Hunter, 2007). Increases in virulence have been shown to be due to point mutations, as mentioned, characterized by an increased ability to transform PrPC to PrPSC (Priem et al., 2014).
A prion disease-resistant PrPC gene has been identified in Papua New Guinea, probably due to a selection pressure caused by the number of cases of kuru in the middle of the nineteenth century. This polymorphism offers complete protection to the mutant PrPSC, and gives researchers a greater understanding of the mechanisms behind prion disease, as well as potential therapeutic avenues (Zheng et al., 2018).
Creutzfeldt-Jakob disease is broadly characterized by a rapid dementia in older adults, and death within a year. This is true for sporadic and familial CJD but acquired CJD presents some variation. Acquired CJD occurs in individuals under 55 and has an incubation period of (on average) 17 years. Occurrence of this disease is very low, at about 1 in 1,000,000 people annually. Since this disease is generally late onset and occurs in individuals over the age of 50, incidence rate for this age group increases to about 3.5 cases per million, worldwide (Centers for Disease Control, 2018). In the United States, studies show that women are more likely to develop CJD, but this can be attributed to the longer age and likelihood of women living longer than men. Statistics also show a higher incidence rate in whites than in people of color. This could be due to a genetic polymorphism that makes white populations more susceptible, but it is also likely that it is just underreported in other ethnic populations. Classic CJD is the most common form of CJD seen, with about 85% of cases being sporadic and 5-15% being familial or inherited (Centers for Disease Control, 2018).
Variant CJD statistics are invariably linked to BSE occurrence in the country that they occur. By 2008, the UK had reported 184,000 cases of BSE in their cattle and 186 cases of vCJD (Holman et al., 2010). In North America, the most recent statistics show only 26 cases of BSE have been reported, and only 4 reported cases of vCJD in the United States (Centers for Disease Control, 2018). While the statistics for the UK are ten years older, it is undeniable that there is a greater risk of contraction of vCJD in the UK than in the US.
Table 1. This is a table showing the age groups, sex, and races affected by CJD. It also lists deaths, and death rate. These values are from the years 1979-2006. (Holman et al., 2010)
Societal and Economic Impact
Acquired CJD has the highest social and economic impact of the three types of CJD. Due to the high prevalence of BSE in cattle in the UK, steps had to be taken to control transmission in farms and industry. This leads to an economic burden on cattle and livestock owners, as diseased animals need to be quarantined and killed. Approximately three quarters of a million cattle were slaughtered during the UK BSE epidemic and potentially consumed by UK residents and travelers during that time (Belay & Schonberger, 2005). The long and varied incubation period of vCJD lends itself to be easily disguised and underreported. Iatrogenic CJD (acquired through medical practices) is also a danger due to the high resistance of PrPSC to destruction. Patients have been diagnosed with iCJD after undergoing a variety of medical procedures. Two girls under the age f 25 were diagnosed with iCJD after undergoing electroencephalographic (EEG) procedure, and four others from usage of other contaminated pieces of neurological equipment. About ten individuals were diagnosed after receiving corneal grafts. About 165 individuals who received human growth hormone developed iCJD. While the numbers of individuals who contracted iCJD aren’t necessarily high, it is of great concern. It is near impossibly to accurately diagnose CJD in patients before undergoing medical procedures, and decontamination of equipment in incredibly difficult. Infected and contaminated equipment often needs to be replaced, placing a large economic and financial burden on hospitals and medical centers. Contamination of stock piles of human growth hormone also places a large societal burden on those receiving these hormones, as they are at constant risk of contracting CJD (Belay & Schonberger, 2005).
The main issue with prion diseases is the lack of research, lack of knowledge and lack of international disease tracking. The history of this disease isn’t very long and is riddled with disbelief in the scientific community – it was about 10 years after Prisiner proposed the term prion and confirmed that the etiology of this disease is actually a protein that the scientific community began to believe him. Difficulty of researching the disease plays a large role in the amount of varied research available. Many of the papers I found were from the mid 1990s to mid 2000s, largely due to the increased public notice of CJD and due to the increase in cases of vCJD in the UK.
A potential avenue for future control opportunities is to take advantage of the existing knowledge pertaining to polymorphisms in the PrPC gene that allow for increased resistance to the infectious mutation, and genetically engineer livestock to have this resistance. This could also be pursued in humans, but that would be far down the road. This could lessen the bovine spongiform encephalopathy burden in countries with high occurrence, and in turn lead to a lessened load of vCJD cases in those countries.
There is also the dire need for a treatment that can help reduce the PrPSC load in individuals with prion diseases. This disease has a very fast pathogenesis and leads to death within a year of disease onset. This rapid deterioration could be either prolonged, or avoided, with more research and better treatment options.
Another potential avenue for research would be genetic sequencing of the PrPC gene. This could help identify individuals with the infectious mutation and potentially genetically engineer their genomes to fix the issue. This could be used generationally, to potentially eliminate inherited CJD altogether.
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