Life of Prion

Or What Links Cannibalism to Foot and Mouth Disease?

 

 By Simona Zahova

Edited by Jon & Sophie

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A peculiar group of proteins, prions, have earned a mythical status in sci-fi due to their unorthodox properties and unusual history. These deadly particles often play a villainous role in fiction, appearing in the Jurassic Park franchise, and countless zombie stories. Even putting apocalyptic conspiracies aside, prions are one of the wackiest products of nature, with a history so remarkable it needs no embellishment. Tighten your seatbelts, we are going on a journey!

Our story begins in Papua New Guinea, with the Fore tribe. The Fore people engaged in ritualistic funerary cannibalism, consisting of cooking and eating deceased family members. This tradition was considered necessary for liberating the spirits of the dead. Unfortunately, around the middle of the 20thcentury, the tribe experienced a mysterious deadly epidemic, that threatened to wipe them out of existence. A few thousand deaths were estimated to have taken place between the 50s and the 60s, with the diseased exhibiting tremors, mood swings, dementia and uncontrollable bursts of laughter. Collectively, these are symptoms indicative of neurodegeneration, which is the process of progressive death of nerve cells. Inevitably, all who contracted the disease died within a year (Lindenbaum 1980). The Fore people called the disease Kuru after the local word for “tremble”, and believed it was the result of witchery.

Meanwhile, Australian medics sent to investigate the disease reported that it was psychosomatic. In other words, the medics believed that the tribe’s fear of witchcraft had caused massive hysteria that actually had an effect on health (Lindenbaum 2015). In the 60s, a team of Australian scientists proposed that the cannibalistic rituals might be leading to the spreading of a bug causing the disease. Since the Fore tribe learned about the possible association between cannibalism and Kuru, they ceased the tradition and the disease rates drastically reduced (Collinge et al. 2006). However, the disease didn’t disappear completely, and the nature of the mysterious pathogen eluded scientific research.

Around the same time, on the other side of the globe, another epidemic was taking place. The neurodegenerative disease “scrapie” (aka “foot and mouth disease”) was killing flocks of sheep in the UK. The affected animals exhibited tremors and itchiness, along with unusual nervous behaviour. The disease appeared to be infectious, yet no microbe had been successfully extracted from any of the diseased cadavers. A member of the agricultural research council tentatively noted that there were a few parallels between “scrapie” and Kuru (Hadlow 1959). For one, they were the only known infectious neurodegenerative diseases. More importantly, both were caused by an unknown pathogen, which eluded the normal methods of studying infectious diseases. However, due to the distance in geography and species between the two epidemics, this suggestion didn’t make much of a splash at the time.

The identity of this puzzling pathogen remained unknown until 1982, when Stanley Prusiner published an extensive study on the brains of “scrapie” infected sheep. It turned out that the culprit behind this grim disease wasn’t a virus, a bacterium, or any other known life form (Prusiner 1982). Primarily, the pathogen consisted of protein, but didn’t have any DNA or RNA, which are considered a main requirement for life. To the dismay of the science community, Prusiner proposed that the scrapie “bug” was a new form of protein-based pathogen and coined the term “prion”,short for “proteinaceous infectious particle”. He also suggested that prions might be the cause not only of scrapie, but also of other diseases associated with neurodegeneration like Alzheimer’s and Parkinson’s. Prusiner was wrong about the latter two but was right to think the association with “scrapie” would not be the last we hear of prions. Eventually, the prion protein was confirmed to also be the cause of Kuru and a few similar diseases, like “mad cow” and Creutzfeldt-Jacob disease (Collins et al. 2004).

Even more curiously, susceptibility to prion diseases was observed to vary between individuals, leading to the speculation that there might be a genetic component as well.  The mechanism behind this property of the pathogen remained a mystery until the 90s. Once biotechnological development allowed the genetic code of life to be studied in detail, scientists demonstrated that the prion protein is actually encoded in some animal genomes and is expressed in the brain. The normal function of prions is still unclear, but some studies suggest they may play a role in protecting neurons from damage in adverse situations (Westergard et al. 2007).

How does a protein encoded into our own DNA for a beneficial purpose act as an infectious pathogen? Most simply put, the toxicity and infectiousness only occur if the molecular structure of the prion changes its shape (referred to as unfoldingin biological terms). This is where heritability plays a part. Due to genetic variation, one protein can have multiple different versions within a population. The different versions of the prion protein have the same function, but their molecular architecture is slightly different.

Imagine that the different versions of prion proteins are like slightly different architectural designs of the same house. Some versions might have more weight-bearing columns than others. Now let’s say that an earthquake hits nearby. The houses with the extra weight-bearing columns are more likely to survive the disaster, while the other houses are more likely to collapse.

What can we take away from this analogy? A person’s susceptibility to prion diseases depends on whether they have inherited a more or less stable version of the prion protein from their parents. In this case, the weight-bearing column is a chemical bond that slightly changes the molecular architecture of the prion, making it more stable. Different prion diseases like Kuru and “scrapie” are caused by slightly different unstable versions of the prion protein, and their symptoms and methods of transmission also differ.

Remarkably, a study on the Fore people from 2015 discovered that some members of the tribe carry a novel variant of the prion protein, that gives them complete resistance to Kuru (Asante et al. 2015). Think of it this way: if people inherit houses of differing stability, then some members of the Fore tribe have inherited indestructible bunkers. Evolution at its finest! It isn’t quite clear what is the triggering event behind the “collapsing” or unfolding of prions. Once a prion protein has unfolded, it leads to a domino effect, causing the other prions within the organism to also collapse. As a result, a bunch of unfolded proteins accumulate in the brain, which causes neurodegeneration and eventually death.

One explanation of why neurons die in response to prions “collapsing” is that cells sense and dislike
unfolded proteins, triggering a chain of events called the unfolded protein response. This response stops all protein production in the affected cells until the problem is sorted out. However, the build-up of pathogenic prions is an irreversible process and it happens quite quickly, so the problem is too big to be solved by stopping protein production. In fact, it is a problem so big that protein production remains switched off indefinitely, and consequently neurons starve to death (Hetz and Soto 2006).

We have established that prions are integral to some animal genomes and can turn toxic in certain cases, but how can they be infectious too? Parkinson’s and Alzheimer’s are also neurodegenerative diseases caused by the accumulation of an unfolded protein, but they aren’t infectious. The difference is that prions have a mechanism of spreading comparable to viruses or bacteria.  One might wonder why one of our own proteins has a trait that allows it to turn into a deadly pathogen. Perhaps this trait allowed proteins to replicate themselves before the existence of DNA and RNA. Or, in other words, this might be remainder from before the existence of life itself (Ogayar and Sánchez-Pérez 1998).

To wrap things up, prion diseases are a group of deadly neurodegenerative diseases that occur when our very own prion proteins change their molecular structure and accumulate in the brain. What makes prions unique, is that once they unfold, they become infectious and can be transmitted between individuals. The study of their biomolecular mechanism has not only equipped us with enough knowledge to prevent potential future epidemics, but also offers an exciting glimpse into some of the secrets of pathogenesis, neurodegenerative diseases, evolution and life. Most importantly, we don’t need to worry about the zombies anymore. Let them come, we can take ‘em!

 

References:

Asante, E. A. et al. 2015. A naturally occurring variant of the human prion protein completely prevents prion disease. Nature522(7557), pp. 478-481.

Collinge, J. et al. 2006. Kuru in the 21st century—an acquired human prion disease with very long incubation periods. The Lancet367(9528), pp. 2068-2074. doi: https://doi.org/10.1016/S0140-6736(06)68930-7

Collins, S. J. et al. 2004. Transmissible spongiform encephalopathies. The Lancet363(9402), pp. 51-61.

Hadlow W.J. Scrapie and kuru. Lancet. 1959:289–290.

Hetz, C. A. and Soto, C. 2006. Stressing out the ER: a role of the unfolded protein response in prion-related disorders. Current molecular medicine6(1), pp. 37-43.

Lindenbaum, S. 1980. On Fore Kinship and Kuru Sorcery. American Anthropologist82(4), pp. 858-859.

Lindenbaum, S. 2015. Kuru sorcery: disease and danger in the New Guinea highlands. Routledge.

Ogayar, A. and Sánchez-Pérez, M. 1998. Prions: an evolutionary perspective. Springer-Verlag Ibérica.

Prusiner, S. B. 1982. NOVEL PROTEINACEOUS INFECTIOUS PARTICLES CAUSE SCRAPIE. Science216(4542), pp. 136-144. doi: 10.1126/science.6801762

Westergard, L. et al. 2007. The cellular prion protein (PrP C): its physiological function and role in disease.Biochimica et Biophysica Acta (BBA)-Molecular Basis of Disease1772(6), pp. 629-644.

 

 

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