Prions: When proteins go awry

What is non-living and doesn’t have DNA –but yet, it can infect, replicate, and eventually kill you? The answer… a simple type of protein called a prion.

Prions are a difficult concept to grasp. They’re misfolded protein molecules, but not in the same way other proteins misfold. Prions can infect, causing the normal protein around them to also misfold and become infectious. The misfolded proteins clump together and induce neurodegenerative illness.

Prions, unlike bacteria, viruses, and other pathogens, do not contain DNA or RNA, but they can spread in an infectious manner. Instead of replicating, the misfolded proteins travel around the body, causing normal proteins to misfold.

In this article, I will explain some of the background science on prions and examine how genetic mutations are involved. Finally, I’ll explore some current theories linking Alzheimer’s and Parkinson’s as prion-related diseases.

History and background: Prion diseases

The word prion comes from “proteinaceous infectious particle”.

Although prions were recognized and isolated for the first time in the early 1980s, animal variants of the disease have been known since antiquity. Prions aren’t limited to animals, though. Plants, fungi, and yeast have all been discovered to have prions in recent years.[ref][ref]

Examples of prion diseases include:

bovine spongiform encephalopathy (mad cow disease or BSE)
chronic wasting disease (deer, elk, moose)
scrapie (sheep, goats)
fatal familial insomnia (humans)
Creutzfeldt-Jakob Disease (humans)
kuru (humans)
Gerstmann-Sträussler-Scheinker (humans)

Prions cause fatal, neurodegenerative diseases.

That is a sentence that strikes fear in the hearts of nearly everyone. Human prion disease symptoms tend to strike during mid-life – anywhere from age 28 to 70.

They can arise from eating an animal infected with the disease, and prion diseases can also arise spontaneously or due to genetic mutations.

Creutzfeldt-Jakob Disease (CJD) is a fatal neurodegenerative disease caused by cell death due to prions in the brain. It causes progressive neurodegenerative problems such as tremors, problems with movement, changes in personality, and dementia.[ref]

CJD can have a variety of causes:

Sporadic CJD arises without a known cause (74% – 90% of cases)
CJD can be caused by inheriting a genetic mutation (<15% of cases)
Acquired CJD can be transferred by exposure (<6%)[ref][ref]

Acquired prion disease usually comes from eating an infected animal (e.g., mad cow disease), a blood donation, or dura matter graft from an infected person. (CDC info on CJD)

Brain matter infected with prions cannot be rendered safe by normal means.

Cooking and disinfectants do not destroy prions. Some measures render medical equipment safe after possible prion exposure, which has almost eliminated the transfer of prion disease through surgery.

All of this from a misfolded protein…

Why is protein folding important?

Misfolded protein – somehow, this term brings to mind my failed attempts at origami.

Let me back up a bit and give you some context…

Your genes code for proteins, which make up your body’s structure and functions. Proteins form structural elements in cells, making up the receptors on cell surfaces. The enzymes that cause the biochemical reactions to happen inside cells are proteins.

Proteins are assembled from 20 different amino acids (in humans and most animals).

But they aren’t just long straight chains of amino acids; the order of the amino acids also controls how the protein folds up onto itself. The importance of protein folding is crucial to its function. Therefore, the protein doesn’t function correctly if it isn’t completed correctly. For example, a protein may need a hydrophobic region sticking out to anchor it to the cell membrane. Without being folded correctly, it may not be able to anchor to the right spot.

Quick analogy: Think of Lego blocks as your amino acids. You could take those blocks and make them into a truck — or — a dinosaur. The blocks are the same, but they are assembled differently. Any 4-year-old can tell you that the truck is not the same as a dinosaur.

With proteins, different conformations change or eliminate their function.

Proteins are degraded and recycled back into their amino acid components all the time. How long a protein exists in a cell depends on the protein, but the half-life can be from minutes to years. Most proteins hang around for a few days and then degrade.

Misfolded proteins often happen in a cell. They usually are unstable and break down quickly.

It isn’t true of prions… Prion proteins are structurally stable and resist denaturing (being broken down). They stick around even though they aren’t functioning correctly. This stability, plus their ability to cause normal proteins to also misfold, is the crux of the problem.

Here is a good article on protein folding if you want to know more.

What do prions do in the brain and elsewhere?

The protein that makes up the prions is coded for by the PRNP gene. The normal PRNP protein exists throughout all tissues in the body but is found at higher concentrations in the brain. The physiological functions of the PRNP protein in its normal form include myelin maintenance, circadian rhythm regulation, cellular differentiation, immune regulation, copper utilization, iron uptake and transport, and possibly a role in memory formation.[ref] Oddly, with all those different functions, the PRNP protein is one that we (and animals) can live without.

Research also points to the PRNP protein playing a role in stopping viral replication. It is thought to be part of the brain’s immune response to viruses.[ref] A 2021 animal study found that a neurotropic strain of influenza A could induce the conversion of normal PRNP proteins into prions.[ref]

When the PRNP protein misfolds, it becomes a prion. This misfolding could be due to an inherited mutation, which arose when DNA damage happened to a cell or through the ingestion of tissue from an infected animal.

These misfolded but stable prions can recruit normally folded PRNP to become misfolded. Since they don’t break down and clear out, they can build up in the brain and nervous tissue. This lack of clearance eventually causes cell death and tissue damage in the brain.

When looking at samples of brain tissue infected with a prion disease, it has small holes in it and a spongy appearance.

It takes many months to several decades for enough of the misfolded proteins to build up. It is an exponential growth curve that is slow to start but then builds quickly at the end.

Evolutionary biologists explain that prions are a way that genetically identical cells can have diverse phenotypes. Essentially, proteins can pass along information without using traditional means of inheritance such as RNA or DNA. For example, prions in yeasts allow identical cells to adapt to environmental changes.[ref]

Hereditary prion diseases:

Inherited mutations in the PRNP gene cause genetic or hereditary prion disease. Between 1 to 2 people per million are diagnosed each year with this rare disease.[ref]

Not only are there mutations that cause familial CJD, but there are also genetic mutations that completely prevent prion diseases.[ref]

Traditionally, hereditary prion diseases were thought to be passed from parent to child, with the offspring having a 50/50 chance of getting the disease.

But wait… the science here has gotten a little more interesting on this topic since the advent of inexpensive genetic testing.

A 2016 study examined the number of individuals who carried a PRNP mutation in two different data sets. One data set had 60,000 people, and the other was 500,000+ people from 23andMe. The study investigated the number of PRNP pathogenic mutations carried in the populations. One big part of this was to see how penetrance for a disease carries out in a population. Inherited mutations in the PRNP gene were always thought to cause prion diseases.

The study results showed that prion mutations were about 30 times more common in the genetic data than expected.[ref] So why do some people carry the mutation that supposedly causes CJD, yet don’t seem to have the disease? That is one question researchers are still trying to answer.

Another question researchers raise is whether other neurodegenerative diseases are a type of prion disease.

Alzheimer’s and Parkinson’s Diseases. A link to prions?

For the past few years, researchers have been bringing together the idea that Alzheimer’s and Parkinson’s are prion-like diseases.

A 2015 article in the journal Science highlighted and explained the overlap between prion disease and common neurogenerative diseases.[ref]

Research now points to Alzheimer’s and Parkinson’s disease being similar to prion disease in a lot of ways. Both diseases are caused by abnormal proteins causing damage to the brain.

Similar to Creutzfeldt-Jakob Disease (CJD), most Alzheimer’s and Parkinson’s disease cases are sporadic – not caused by rare mutations in the APP or SNCA genes. Both diseases are caused by a build-up of insoluble proteins in the brain over decades. Both are neurodegenerative diseases that progress without a cure.

However, one big difference is that Alzheimer’s and Parkinson’s diseases are not considered transmissible or contagious, although some animal studies question this. Infectious sources of CJD (e.g., eating cow brains infected with mad cow disease) show that it can pass from one source to another. However, not everyone who eats infected meat (cow, deer, etc.) gets the disease. Infectiousness is considered a hallmark of prion diseases.

The evidence cited for tau protein tangles in AD being similar to prions includes that they “spread along neural pathways from one brain region to another”. Additionally, the α-synuclein protein in Parkinson’s forms Lewy bodies that “spreads along neural pathways in the brain, beginning in the dorsal motor nucleus of the glossopharyngeal and vagal nerves, the olfactory bulb, and the anterior olfactory nucleus”. And mouse studies show that injecting α-synuclein from Lewy-body dementia patients into the mice brains causes the formation of mouse α-synuclein inclusions. [ref]

There are genetic connections between Alzheimer’s and Creutzfeldt-Jakob Disease. A genetic variant in the PRNP (prion protein) gene has decreased the risk of CJD and Alzheimers. Not all studies back up the connection, though.[ref][ref] Additionally, a variant in the protein that cleaves the amyloid precursor protein increases the risk of CJD.[ref]

Some researchers speculate that prions or prion-like proteins could be at the root of all neurodegenerative diseases. In fact, recent research showed Alzheimer’s like amyloid-beta plaque and tau tangles in 6 out of 8 brain autopsy results of people who had Creutzfeldt-Jacob disease. The results were remarkable because the brains were from people who died in middle age – long before Alzheimer’s pathology should ever appear in the brain.[ref]

Recently, research has linked the α-synuclein protein that causes Parkinson’s with the pathology of Alzheimer’s disease. Over half of the brain autopsies of people with AD also show high concentrations of α-synuclein aggregates. And 90% of people with the early-onset hereditary forms of AD have aggregated α-synuclein deposits in the amygdala. But while these co-exist and perhaps enhance the pathology, it has also been found in about 25% of normal brain autopsy reports that individuals without dementia had Lewy body or Alzheimer’s pathology in their brain.[ref]

Intriguingly, animal studies show that deleting the PRNP gene prevents the hereditary, early-onset form of Alzheimer’s.[ref]

Prion Diseases Genotype Report:

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PRNP gene:

The PRNP gene encodes the normal protein that, when misfolded, becomes a prion. There are several common genetic variants in this gene, as well as rare mutations that cause familial CJD.

Check your genetic data for rs1799990 (23andMe v4, v5; AncestryDNA):

A/A: typical disease risk
A/G: reduced risk of sporadic Creutzfeldt-Jakob disease (CJD), possibly reduced risk for late-onset Alz.
G/G: protective against sporadic CJD, and possibly reduced risk for late-onset Alz.[ref][ref][ref][ref]

Members: Your genotype for rs1799990 is —.

The following are pathogenic prion disease mutations found in 23andMe data. For prion diseases, you only need one copy of the mutation. 23andMe does not guarantee accuracy at the level of clinical testing. Thus, if you find that you carry one of the mutations below, it could very well be due to an error in your genetic data. Don’t make medical decisions based on 23andMe data – get a clinical test done to verify. Please also note that not all PRNP mutations are covered in 23andMe data, so you can’t use them to rule out a disease.

Check your genetic data for rs11538758 (23andMe v4, v5; AncestryDNA):

C/C: typical
C/T: possible pathogenic allele for Gerstmann-Straussler-Scheinker syndrome (double-check your genetic data with a clinical test)[ref]

Members: Your genotype for rs11538758 is —.

Check your genetic data for rs28933385 (23andMe v4; AncestryDNA):

G/G: typical
A/G: E200K, possibly pathogenic allele for CJD, familial fatal insomnia; double-check a clinical-grade test[ref][ref]

Members: Your genotype for rs28933385 is —.

Check your genetic data for rs74315405 (23andMe v4 – i5004356; AncestryDNA):

T/T: typical
C/T: possible pathogenic allele for Gerstmann-Straussler-Scheinker syndrome (double-check your genetic data with a clinical test)

Members: Your genotype for rs74315405 is — or for i5004356 is —.

In addition to the PRNP gene mutations, research indicates other genes slightly influence susceptibility to prion diseases. Keep in mind that if your risk of getting a prion disease is 1 in a million, a 20% increase in the risk makes your risk 1.2 in a million. These are included because they are interesting, not because they are clinically important.

ZBTB38 gene: encodes a zinc finger transcriptional activator that binds methylated DNA.

Check your genetic data for rs9857275 (23andMe v4, AncestryDNA):

A/A: slightly decreased risk of prion diseases[ref]
A/C: slightly decreased risk of prion diseases
C/C: typical

Members: Your genotype for rs9857275 is —.

SEMA3A gene: encodes a protein vital for neuronal pattern development.

Check your genetic data for rs488333 (23andMe v4; AncestryDNA)

G/G: slightly increased risk of prion diseases[ref]
A/G: slightly increased risk of prion diseases
A/A: typical

Members: Your genotype for rs488333 is —.

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