Continuing our focus on the intricate world of neuroscience, this week’s TVF blog looks at rare prion diseases.
Introduction
Prion diseases, or transmissible spongiform encephalopathy, are rare diseases which occur when the normal prion protein, found on the surface of many cells, folds abnormally and forms clumps in the brain. These clumps cause brain damage and death. Sadly, prion diseases are 100% fatal.1,2
Prions
The word prion comes from proteinaceous infectious particle, and prion diseases occur in both humans and animals. These can be genetic and account for 15% of the human prion diseases e.g. Fatal Familial Insomnia, Gerstmann-Straussler-Scheinker Syndrome, and Creutzfeldt Jakob Disease (CJD): all of which cause rapid and inevitable neurodegeneration and death. The time to death can vary depending on the inherited form of the disease. For instance, in Gerstmann-Straussler-Scheinker disease, the average survival rate is 5 years, which can range from 2 to 10 years following diagnosis.3 Meanwhile, fatal familial insomnia and CJD can be fatal in as little as 6–8 months from the onset of first symptoms.4,5,6,7 CJD comes in both genetic and acquired forms, and is named after two 1920s German neuropathologists: lfons Maria Jakob and Hans Gerhard Creutzfeldt.8
Read more about Creutzfeldt here: https://www.scielo.br/scielo.php?script=sci_arttext&pid=S0004-282X2021000100084&lng=en&nrm=iso&tlng=en
The second type of CJD can be acquired from food and is known as the human form of mad cow disease, or variant CJD (vCJD). vCJD is probably the most infamous of the two known acquired prion diseases. The other known acquired prion disease was Kuru (a form of transmissible spongiform encephalopathy), which affected the Fore people of Papua New Guinea and involved the transmission of prions via ritualistic endocannabilism (anthropophagy). Kuru led to symptoms such as tremors and loss of coordination from neurodegeneration. Sadly, death usually occurred within two years and thankfully, due to the Fore people ending their anthropophagy practices, there hasn’t been a case of Kuru for over a decade.9
Prions are found in the membranes of all cells, read more here: https://www.scientificamerican.com/article/what-is-a-prion-specifica/
The normal prion protein comes in two forms. Some individuals have the M polymorphism, where amino acid methionine (M) is at position 129 in the amino acid chain, some have valine (V) at position 129 and some have both forms of the normal prion.10
The vCJD prion interacts with normal prions and ‘passes-on’ the deformed shape. The M prions are more susceptible to deformation by the vCJD prion, so if there are less M prions it takes longer for the disease to develop.10 It is estimated that a third of the UK population possess two copies of M (homozygous) at position 129. Prion disease susceptibility and the time it takes for individuals to develop the disease may be affected by other genes, and it is likely that vCJD cases may have unusual genetic combinations that remain to be characterised.11
Mad Cow Disease
Consuming animal products that are contaminated with a prion can transmit a prion disease to humans. In the case of vCJD, eating a cow infected with BSE would sometimes transmit the human variant, vCJD, to the person. The cow form of vCJD is called Bovine spongiform encephalopathy (BSE). Cows in Britain began to suffer from BSE in 1986. By, 1988 there were over 400 cows with the condition and by 1993 there were over 120,000. It was found that cows became infected with BSE as a result of being fed cow carcasses.10,11
The British government failed to act decisively about whether BSE was a threat to humans and by the time it was deemed a serious risk to public health it was too late, as members of the public were already being infected with vCJD.10,11
The British cases of vCJD began in 1994 and were linked to infected cattle. Unlike the usual form of CJD, vCJD affected very young people and the first case was in a 19 year-old named Stephen Churchill.12 The disease began as increased aggression, personality changes, episodic memory loss and gait ataxia. Churchill experienced severe mental decline, followed by rapid dementia. He died delirious and foaming at the mouth in 1995 due to the vCJD protein infecting his brain, leaving it riddled with tiny holes. If you looked at the brain of a person with vCJD down a microscope, you would find it looked a little like a sponge.10
The initial wave of vCJD only affected people who have the M prion (the prion type which can be infected by the vCJD prion) and included a strict vegetarian (there are some who believe that a particular cluster of cases developed from cattle carcass slurry being poured down a well. www.mad-cow.org).10,12 However, the tale does not end there. As late as the year 2000, a calf born after the anti-BSE measures were put in place, was found to be infected with BSE.13
Read more about the timeline here: http://news.bbc.co.uk/hi/english/static/special_report/1999/06/99/bse_inquiry/default.stm
The first MV individual (i.e. someone with both of the two possible types of prion), whose vCJD had taken decades to develop due to there being less M prions for the vCJD prion to deform, got ill and died of the disease in 2014.10 Although there are some who suspect that the second wave started earlier, with cases mistaken for the non-variant form of CJD, it is likely that the next wave of vCJD cases will begin in earnest soon.14
It has been theorised that exposure to vCJD was so extensive that if vCJD was more infectious there could have been millions of deaths. Even to this day, those who ate beef before the new beef controls were put in place (i.e. the controls which stated farmers must not feed dead cows to other cows), could still develop the disease. Similarly, there may be people infected via blood transfusion, known as iatrogenic CJD. Interestingly, more than 100 cases of acquired (iatrogenic) CJD occurred subsequent to intramuscular injection with human cadaveric growth hormones, which were tainted with CJD prions.15 The time it takes to develop the disease (i.e. the disease incubation period) can vary, with a mean of about 10–15 years.
As mentioned previously, the effect of codon 129 genotype may modify the mean incubation period and the overall susceptibility. For example, the earliest cases of CJD related to iatrogenic growth hormone in the UK were homozygous for valine at prion codon 129. This genotype/genetic makeup is observed in 11% of white people.16 Based on the evidence discussed it is likely that genetic and iatrogenic forms of CJD exhibit differences in disease expression and clinical manifestation. Thorough investigations are warranted to understand the variable disease trajectories in prion’s disease and respective treatments, as we haven’t seen the last of mad cow disease and vCJD yet.
Conclusion
With prion disease on the increase in the animal kingdom, awareness of animal-human prion transmission is increasingly important. In particular, prion diseases are becoming more common among the deer and elk populations, which may be able to cross into human populations analogous to the way that vCJD crossed the species barrier to infect humans.17,18 Since the disease is transmissible and fatal, it remains incurable to this day.
Future research will be pivotal in understanding the mechanisms underlying the disease and developing therapeutics that can delay the disease progression. Since prion diseases may share common disease mechanisms to neurodegenerative diseases including Alzheimer’s disease (which is the most common cause of dementia), it is likely that therapeutics developed for prion diseases could also be used for other more commonly occurring neurodegenerative diseases.
At TVF we have significant expertise in rare diseases and neuroscience. This puts us in prime position to aid in the investigation, development, branding, and marketing of potential therapeutics in the field of prion disease. If you would like to find out more about TVF’s business offerings, get in touch!
By Stephanie James