A Wrinkle in the Mind: How Prions Infect the Brain

Sufana Noorwez

Illustrations by Iris Li

It was an average December in MT’s household. She was shopping, meeting up with her family, and getting excited for the holidays ahead. The holidays passed by uneventfully, but all of a sudden, she started to notice something strange. At first, the symptoms were subtle enough; she found it harder to do some simple math and to complete normal chores. Over time, the symptoms worsened. MT was confused all of the time, her movements became jerky, and her vision started to blur. Her strange new symptoms resembled those of many common neurological diseases, and yet no matter how many tests they ran, her doctors could not pin down a specific cause or diagnosis. As the days passed, MT’s condition continued to decline; she began to have visual hallucinations and delusions, and started to suffer from seizures [1]. At this point, MT’s doctors began to piece together the puzzle: MT had a rare type of infection called a prion disease, and her prognosis was not good. About 70% of the time, death occurs within one year of symptom onset [2]. In MT’s case, the specific disease was called ‘variant Creutzfeldt-Jakob disease,’ the human manifestation of bovine spongiform encephalopathy, more famously known as ‘mad cow disease’ [3]. Prion diseases are rare and unique, but terrifying; they are nearly untreatable and extremely deadly. Unbeknownst to their victims, prions invade the brain and multiply, presenting a fascinating case of what can go wrong when your body betrays you. 

From Protein to Prion

Prion disease can wreak havoc on essential molecules in our bodies called proteins [4, 5]. As the biochemical workhorses of the human body, proteins are responsible for much of the activity within our cells. Proteins facilitate chemical reactions, make up the structure of our tissues, and move materials around our bodies. The structures of proteins must be carefully regulated during their creation because protein structure is inextricably linked to function. Even the smallest mistake in form can render proteins incapable of partaking in their crucial roles, including building our body’s tissues, protecting against diseases, and sending signals throughout the body. Proteins need to fold into complex, three-dimensional shapes in order to become fully functional. The folded structure of proteins is determined by a series of chemical reactions, with various conditions — such as temperature — kept constant to ensure proper protein folding [4]. Think of protein folding like making an origami boat. If you have the correct instructions to form the shape of the boat and you make smooth, even creases, your boat will have good form. The boat’s structure ensures that it can carry out its function: floating. If you rush through the folding, making haphazard folds and creases, your origami boat may no longer resemble a real boat. The boat may even sink when you place it in water. Similarly, the structure of proteins and the way that they are folded affects their function [4]. 

One extreme example of what can happen when proteins fold incorrectly is the development of prion diseases, in which misfolded proteins cause widespread degradation of the brain [5, 6, 7]. The accumulation of misfolded proteins causes cells in the nervous system to gradually become dysfunctional and eventually die, via a process called neurodegeneration. The same process is seen in diseases like Alzheimer’s and Parkinson’s disease [8, 9]. A prion is a misfolded version of a specific protein called PrP, or cellular prion protein, which is present in all human brains [7]. This misfolded protein, called a ‘prion’ or PrPSC, is the pathogenic, infectious version of the normal PrP —meaning that it can cause and spread disease. The misfolding of PRPSC can happen because of a mutation in one’s genetic code, which arises due to either a spontaneous misfolding or exposure to an already misfolded PrPSC [7]. In all of these cases, the genetic code — which provides the instructions for protein folding — is overridden by PrPSC, allowing the misfolded protein form to prevail [10, 11, 12]. This is similar to the instruction manual for folding an origami boat. Incorrect instructions, resulting in even just one error in a fold, can have drastic effects on the shape and function of the boat. 

The real danger with prions lies in their ability to spread their misfolded state to other proteins of the same type [13, 14, 15]. Most proteins require a ‘blueprint’ from another protein of the same kind in order to initiate their own folding [16, 17]. Therefore, during protein folding, new PrP latch on to their nearest lookalike neighbor and use their structure as a guide for how they should fold. In the case of prions, when there is one PrPSC, PrP uses this misfolded protein as a template, resulting in the misfolding of the new protein as well. This process is a domino effect: the misfolding of one PrP rapidly causes the misfolding of other PrP in the vicinity [13, 18]. When enough PrP are misfolded, sticky clusters of prions, called plaques, are formed in the brain [19]. 

Plaques Lay Siege to the Brain 

To understand the effects of prion diseases, it’s crucial to understand the protein that the disease affects, PrP. PrP has a variety of important functions within the mammalian brain, such as maintaining the electrical activity of neurons, and facilitating roles in cell signaling, cell adhesion, and the production of new neurons [7, 20, 21]. PrP may also be involved in our sense of smell and the efficiency of signaling between neurons [7, 22, 23, 24]. Despite the varied functions of PrP, the protein does not seem to be necessary for mammalian survival; complete removal of the protein has no apparent effect on health in a rodent model, although it may minorly affect processes involving PrP [7, 20]. As such, the most crucial, deadly symptom of prion diseases is not the loss of function of PrP, but rather the formation of amyloid fibers and plaques within the brain caused by PrPSC [25]. Amyloid fibers are long, fibrous strands of sticky protein clusters that form once PrP misfolds into PrPSC and begins to accumulate. A collection of these fibers is called an amyloid plaque, and are the structures primarily involved in prion disease neurodegeneration [18, 26, 27, 28]. An accumulation of fibers and plaques can have devastating effects on the cells of our brains, causing neuron death [6, 29]. The backlog of misfolded proteins — which the cell has already tried and failed to get rid of — clog up the protein synthesis center of the cell and prevent the synthesis of more essential proteins, leading the cell into a death pathway [6]. Additional ways through which the conversion of PrP to PrPSC can cause neuron death is by degrading the junctions between nerve cells where chemical signals pass between single neurons. When neurons are no longer able to carry out their function by relaying signals, they break down, degrading from one end of the neuron, where signals are passed, to the other end, eventually leading to cell death [6, 30]. This mechanism of neuron death is unique to prion diseases; neurons usually start degenerating and then stop transmitting signals [6]. The rapid death of neurons is what leaves behind the brain holes characteristic of prion diseases [6, 31]. Finally, brain swelling — caused by our immune system’s attempts to clean up plaques — also contributes to neurodegeneration [32]. Although there are a variety of small effects PrPSC has on the brain, the death of neurons seems to be the largest contributor to the fatal symptoms individuals with prion disease experience [6]. If signal communication is compromised, one may experience a loss of motor function, as well as the onset of dementia, headaches, and behavioral changes; this is all characteristic of prion diseases [2].

From Prion to Person 

Prion diseases are exceedingly rare, and the average person will never have to worry about contracting one and experiencing its lethal effects [33, 34, 35]. Creutzfeldt-Jakob disease (CJD) — the human version of mad cow disease — is the most common human prion disease, and was only detected in about one in a million people in the United States between the years of 1979 and 2006 [33]. To put this in perspective, your chances of dying in a car accident are 10,000 times higher than dying from a prion disease, or about one in a hundred [36]. However,  prion diseases are still devastating for the unlucky few that encounter them. In order to understand how prion diseases work, we have to understand how they are transmitted. As the name ‘mad cow disease’ suggests, many prion diseases originate from animals. In the 1980s, an outbreak of ‘mad cow disease’ in the United Kingdom led to the diagnosis of over 100 cases of CJD by 2006 [12]. Infection likely occurred via the consumption of contaminated beef, particularly cuts of meat that contained nervous system tissue, where infectious prion proteins are most highly concentrated [37]. Cattle are not the only culprits either, as prion diseases have been documented in sheep, goats, deer, cats, and even primates [38]. Prions are highly transmissible in animals, and transmission can occur through contact with feces, urine, blood, and saliva [39, 40, 41]. 

Prion diseases have also been documented to pass from parents to children through genetic inheritance [42]. Two well-known examples of this mode include familial Creutzfeldt-Jakob disease, which exhibits similar symptoms to regular CJD, and fatal familial insomnia, a disease which renders victims unable to sleep and leads to their mental and physical deterioration [10, 43]. Because PrP proteins misfold into PrPSC due to a faulty genetic code, children can inherit this faulty code from their parents, which makes them susceptible to the prion disease as well. Because prion diseases can lay dormant for years before affected individuals notice any symptoms, people may not be aware of their infection until late in life [44, 45]. Prion diseases can also be spread through medical contamination [46, 47, 48]. When PrP misfolds into PrPSC, it folds into a very stable structure that cannot be degraded by the immune system; it also tends to attract other PrPSC [49]. This stability means that when medical instruments — such as those used in brain surgery or other hospital settings — come into contact with prion-infected tissue, they cannot be decontaminated with standard protocols, which normally clean off any bacteria or viruses [46]. Consequently, prion transmission can occur in hospital settings through surgical equipment and blood transfusions [45]. 

In the rarest of cases, prion diseases have been passed from human-to-human through cannibalism [50]. In the case of the Indigenous Fore tribe in Papua New Guinea, ritual cannibalism was a common religious practice intended to free the spirits of deceased tribal members [51]. The Fore tribe also suffered disproportionately from symptoms commonly associated with neurodegenerative diseases — symptoms we now know are because of a prion disease transmitted to tribe members via consumption of the brains of deceased tribe members [52]. This disease came to be known as Kuru, which is the Fore word for ‘shiver,’ as well as a fitting name for one of the hallmark symptoms of the condition: shivering [53]. Once the prion disease impacting the Fore was identified as the cause of the aforementioned symptoms, the tribe worked to decrease the incidence of ritual cannibalism as a mortuary practice in order to decrease the spread of Kuru [50].

Different Mechanisms, Similar Outcomes: Prions, Alzheimer’s, and Parkinson’s

As mentioned earlier, one unique characteristic of prion diseases is their similarity to other neurodegenerative diseases, such as Alzheimer’s and Parkinson’s disease. The amyloid fibers and subsequent amyloid plaques caused by prion diseases are similar to the same fibers and plaques characteristic of Alzheimer’s disease [54]. Amyloid fibers build up to form sticky plaques that inhibit brain function. This is similar to spilling orange juice all over the keyboard of your computer; the juice makes the keys sticky, rendering them less useful. Because structures formed in the case of both degenerative and prion diseases are so similar, the symptoms experienced by people who suffer from prion diseases and Alzheimer’s or Parkinson’s are also similar. Some of these symptoms include dementia, loss of motor control, insomnia, and behavioral changes [55, 56, 57, 58]. One major difference between Alzheimer’s and Parkinson’s disease and prion diseases is that the causative agents for the first two are not transmissible between individuals, while they are transmissible between individuals in the case of prion diseases.

A Sticky End

Much is still unknown about prion diseases, their mechanisms, and the full range of their effects [6]. This may be due to their rarity. While there are currently no approved treatments or prevention strategies for any prion diseases, research is still ongoing [34]. In fact, some decontamination strategies have been developed, primarily involving high temperatures or pressures, which aims to remove infectious protein particles from medical instruments [59]. Additionally, to avoid the fate of those who were accidentally infected after consuming nervous system tissue, it is important to avoid consuming meat that may contain infectious particles [60]. Prion diseases like CJD are extremely rare, but understanding their causes and effects allow for a unique view into the inner workings of proteins, the molecules that make up our bodies and allow us to function. Prion diseases hijack one of the most essential life processes — protein folding — and go on to have remarkable effects on the structure and function of the brain. As their sticky strands accumulate, neurons die and the brain is stripped of its ability to send signals. Without the capacity for communication, quality of life rapidly deteriorates, and prions prevail.

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