From mad cow disease to Parkinson's and Alzheimer's: What do we know about prion diseases?

Research on scrapie in sheep conducted in the 1970s led to the discovery of a new type of infectious agent: prions. Initially met with skepticism, the existence of these harmful proteins—which are implicated in numerous fatal, incurable diseases—eventually became widely accepted. Today, evidence even suggests the existence of similar mechanisms in Parkinson’s and Alzheimer’s diseases.

  Creutzfeldt-Jakob disease, fatal insomnia, scrapie, mad cow disease… All these diseases have in common that they attack the brain, progressively degrading it, and that they are incurable. They are also caused by the same type of agent: the prion, a protein that, for reasons still unknown, can become harmful and infect its counterparts, triggering a fatal chain reaction. The discovery in the early 1980s that simple proteins could acquire infectious properties led to a paradigm shift whose effects are still being felt today. Research conducted in recent years suggests that similar mechanisms may be involved in other neurodegenerative diseases, such as Alzheimer’s disease or Parkinson’s disease.  

A Story That Began with Sheep

In science, as in other fields, being a pioneer does not always guarantee immediate success, even when it turns out that one was right before everyone else… Stanley Prusiner learned this firsthand in the early 1980s. This American physician and neurologist had been working with his team since the late 1970s on a disease that attacks the brains of sheep and goats: “scrapie.” This fatal and incurable condition is classified as a spongiform encephalopathy because of its effects: as it progresses, it destroys neurons, so that when the brains of deceased animals are examined during an autopsy, they are riddled with holes, giving them a sponge-like appearance. A decade earlier, in 1967, British biochemist John Stanley Griffith was the first to hypothesize that scrapie might be caused by a protein-based infectious agent. A few years after his death in 1972, Stanley Prusiner and his colleagues set out to prove the validity of this theory. In 1982, they published a description of what, according to their research, was the infectious agent responsible for scrapie. It was, in fact, a single protein, which they named “prion” or PrP. At the time, this work was met with skepticism by the scientific community. It must be said that the only known infectious agents at the time were viruses, fungi, bacteria, or parasites… But in 1985, Stanley Prusiner and his team drove the point home: they demonstrated that the prion is also present in another incurable disease, this time affecting humans—Creutzfeldt-Jakob disease. A few years later, the mad cow disease crisis—a disease also caused by a prion—would finally convince the international scientific community, and Stanley Prusiner was awarded the Nobel Prize in Physiology or Medicine in 1997. Beyond these three diseases, we now know that many other conditions—all of which are incurable—are also caused by prions.  

The prion, an infectious protein responsible for neurodegenerative diseases

Prion diseases are classified as misfolding diseases, since it is the alteration in the 3D structure of the PrP protein that triggers them. To understand the mechanisms involved, it is important to know that proteins are large molecules made up of a chain of smaller molecules called amino acids. They perform countless functions in our bodies; the role of a given protein generally depends on its shape (which itself depends largely on the sequence of amino acids that make it up). The prion protein PrPC is a protein found in the brain that, for reasons still unknown, is capable of changing its 3D structure and adopting a pathological form called PrPSc. Like Anakin Skywalker becoming Darth Vader in the movie Star Wars, the PrPC protein “turns to the dark side of the Force” and becomes PrPSc. However, in its pathological form, PrPSc acquires two new abilities that are responsible for its dramatic effects. First, it is capable of transmitting its pathological 3D structure to the PrPC form. Second, it acquires the ability to accumulate in the form of small toxic aggregates that grow larger to become what are known as amyloid fibers, which are much larger in size. The accumulation of the pathological 3D form of PrPSc is toxic to brain cells: it causes neuron death and the development of neurodegenerative diseases in humans and certain animal species. Unfortunately, to date, the mechanisms controlling the emergence and spread of the pathogenic PrPSc form of the PrP protein remain unclear, and no treatment is available for prion diseases, which are inevitably fatal.  

Human Prion Diseases

Prion diseases are rare conditions that affect the brains of adults. They are also known as transmissible subacute spongiform encephalopathies because they can be transmitted from one person to another. To date, three types of prion diseases affecting humans have been identified: Creutzfeldt-Jakob disease, fatal insomnia, and Gerstmann-Straussler-Scheinker syndrome. - Creutzfeldt-Jakob disease: This is the most common of these rare neurodegenerative diseases, affecting 1 to 2 people per million each year. It is characterized by dementia accompanied by neurological signs such as irregular muscle twitches called myoclonus, balance and gait disturbances, as well as cognitive, memory, orientation, and language impairments. There are three types of Creutzfeldt-Jakob disease: the sporadic form (85% of cases), which occurs spontaneously, with no known cause, after age 60; the hereditary form (10% of cases), caused by the transmission of a genetic mutation; and the acquired form (less than 5% of cases), contracted either as a result of medical procedures such as growth hormone injections (between 1983 and 1988) or dura mater transplants, or through beef meat consumption that was infected (as during the mad cow disease crisis). - Fatal insomnia: This disease can be familial, meaning it has a genetic origin (in which case it is referred to as familial fatal insomnia ), or sporadic. Fatal insomnia is characterized by disturbances in REM sleep that progress to severe insomnia resistant to all treatment, accompanied by disturbances in various automatic bodily functions (digestion, respiration, arterial and venous circulation, blood pressure, etc.). Gradually, movement disorders and dementia develop. The age of symptom onset varies among affected individuals, with some developing symptoms before the age of 20. Death generally occurs within 6 to 18 months after the first symptoms appear. Fatal insomnia affects fewer than one in a million people. - Gerstmann-Straüssler-Scheinker syndrome: Patients with Gerstmann-Straüssler-Scheinker syndrome experience impaired balance and coordination of movement. In its most common form, this disease begins around age 40 and then progresses over several years toward dementia, with worsening neurological symptoms. The number of people affected is very small. - Kuru: This disease affected members of the Fore tribe in Papua New Guinea. Transmitted between individuals through cannibalistic rituals, it disappeared when these practices ceased in the 1950s. In France, 100 to 150 new cases of prion diseases are diagnosed each year. Once the first symptoms appear, these diseases progress rapidly, without remission, until death. In fact, there is no curative treatment; they cannot be cured, nor can their progression be halted. Only symptomatic treatments can alleviate some of the patients’ symptoms.  

Diseases That Also Affect Animals

Unlike other neurodegenerative diseases, prion diseases are unique in that they affect both humans and animals. Among the diseases identified in animals, the best known is probably “mad cow disease,” which affects cattle, hence its name, bovine spongiform encephalopathy. But there is also scrapie in sheep (which also affects goats), which was the focus of the research that first identified prions as infectious agents, as well as other diseases less well-known outside specialist circles, such as chronic wasting disease in deer or prion disease in camels. As the cause of an unprecedented crisis in the 1990s, mad cow disease deserves special attention. First described in 1986 in the United Kingdom, this disease has since been observed in cattle herds in more than 19 countries, including France. According to the World Health Organization, it has affected approximately 200,000 head of cattle (94% of cases were reported in the United Kingdom; in France, approximately 1,000 cases were identified). To date, the exact cause of bovine spongiform encephalopathy has not been clearly determined. Nevertheless, it has been shown that the consumption by cattle of meat-and-bone meal produced from the recycling of carcasses of diseased sheep and cattle was responsible for the increase in the number of cases. Furthermore, this disease is also transmitted between individuals within herds. The bovine prion responsible for mad cow disease is also the cause of a new fatal neurodegenerative disease in humans, known as variant Creutzfeldt-Jakob disease (vCJD). The emergence of this zoonotic disease (transmission of a pathogen from animals to humans) triggered a major health crisis in Europe beginning in the 1990s. Worldwide, there have been 207 deaths among people who developed variant Creutzfeldt-Jakob disease after consuming contaminated beef.

From Prion Diseases to Parkinson’s and Alzheimer’s

There is now substantial evidence that amyloid diseases such as Alzheimer’s and Parkinson’s share a common etiology with prion diseases. Admittedly, these diseases are not caused by the PrP protein: in Alzheimer’s disease, the proteins that change their 3D structure and become pathological are Aβ and tau, while in Parkinson’s disease, it is a protein called α-synuclein. However, although the proteins involved are different, it is now believed that mechanisms similar to those governing the formation and spread of prion amyloid fibers may be involved in these other protein-folding disorders. Researchers are now aiming to identify candidate anti-prion molecules that could be used to treat not only prion diseases but also other misfolding diseases, such as Parkinson’s or Alzheimer’s disease.

This article is published as part of the Fête de la Science (taking place October 4–14, 2024), of which The Conversation France is a partner. This year’s edition focuses on the theme “Ocean of Knowledge.” Find all the events in your region on the Fetedelascience.fr website. Cécile Voisset , Inserm Researcher, PRiME group, LaTIM UMR1101, Inserm, Faculty of Medicine and Health Sciences, University of Western Brittany This article is republished from The Conversation under a Creative Commons license. Read the original article.