Prions: When proteins go awry

What is non-living, doesn’t have DNA but yet can infect, replicate, and eventually cause death?  Sounds like either a really bad riddle or an episode of the Walking Dead…  The answer is a type of protein called a prion.

Prions are a bit hard to wrap my mind around. They are protein molecules that are misfolded, but in a way that is different than other misfolded proteins.

Prions are able to infect, causing the normal protein around them to also misfold.  These misfolded proteins aggregate to cause neurogenerative disease.

But unlike bacteria, virus, or other pathogens, prions don’t contain DNA or RNA, yet can spread in an infectious manner. Instead of replicating, the misfolded proteins spread through somehow causing the normal versions of the protein to become misfolded.

In this article, I’m going to dig into a little of the background science on prions. Then look at how genetic mutations are involved.  Finally, I’ll examine some of the 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”. It was named and first isolated in the early 1980s, but the animal forms of the disease have been known since ancient times. Within the past few years, researchers have also discovered prions in plants, fungi, and yeast. [ref][ref]

In animals, prion disease examples include:

  • bovine spongiform encephalopathy (BSE or mad cow)
  • chronic wasting disease (deer, elk, moose)
  • scrapie (sheep, goats)

Prion diseases are 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.

Creutzfeldt-Jakob Disease, Gerstmann-Sträussler-Scheinker, kuru, and fatal familial insomnia are examples of human prion diseases.

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) or from a blood donation or dura matter graft from an infected person. (CDC info on CJD)

Brain matter that is infected with prions cannot be rendered safe by normal means. Prions are not destroyed by cooking or by disinfectants. There are measures in place that render medical equipment safe after possible prion exposure, which has almost eliminated the transfer of prion disease through surgery.

And all of this is caused by a protein that is simply misfolded…

Why is protein folding important?

Misfolded protein – somehow this term brings to mind my failed attempts at origami. That swan that never looked quite like the directions.

Let me back up a bit and give some background info (that you may already know)…

Your genes code for proteins, and these proteins make up the structure and functions of your body. Proteins form structural elements in cells, and they make up the receptors on cell surfaces. The enzymes that cause the biochemical reactions to happen inside us are (almost) all proteins.

Proteins are assembled from the 20 different amino acids (in humans and most animals). But they aren’t just straight long chains of amino acids, the order of the amino acids also controls how the protein folds up onto itself. This folding is important, and if it isn’t completed correctly, the protein doesn’t function 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. Same blocks – just put together 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 get degraded and recycled back to their amino acid components all the time.  How long a protein exists for in a cell depends on the protein, but the half-life can be anywhere from minutes to years. Most proteins hang around for a few days and then are degraded.

Misfolded proteins happen often in a cell. They usually are unstable and broken down quickly. This isn’t true of prions… Prion proteins are structurally stable and resist denaturing. They stick around even though they aren’t functioning correctly. This, plus their ability to cause the 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 prions are made from is coded for by the PNRP gene. The normal PRNP protein is found throughout the body. It isn’t completely understood yet what its normal function does, but it is thought to play a role in signaling between cells.  [ref]

When the PNRP protein is misfolded, it becomes a prion. This could be due to an inherited mutation, a mutation that arose when DNA damage happened to a cell, or through ingestion of an infected animal.

These misfolded but stable prions can recruit normally folded PNRP to become misfolded. Since they aren’t broken down and cleared out, they can build up in the brain and nervous tissue. This 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.

Hereditary prion diseases:

Genetic or hereditary prion disease is caused by mutations in the PNRP gene that you inherit from a parent.  These diseases are considered very rare with 1 or 2 people per million diagnosed each year.[ref]

Not only are there mutations, though, that cause familial CJD, but there is also a genetic mutation that completely prevents prion diseases. [ref]

Traditionally, prion diseases are 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 cheap genetic testing.

A 2016 study that looked at 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. So a pretty large and varied population to look at. 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. Diseases that are Mendelian inherited (referring to Mendel and his peas) indicated that either one or two copies of the mutation cause the disease. Over the past forty years or so, a lot of the Mendelian disease mutations have been elucidated. An example is cystic fibrosis, which requires two copies of a CTFR gene mutation. Or, back to the topic at hand, prion disease which only takes one copy of the mutation.

This Mendelian model worked great, up until everyone started getting their genomes sequenced…  And researchers are now finding that rare mutations aren’t as rare as they should be. Plus they don’t always seem to cause the disease in an expected manner.

That 2016 study on prion mutations found that they were about 30 times more common in the genetic data than expected. Some of this could be blamed on variants that were falsely identified as being pathogenic for prion disease, but that reasoning only explains a small portion of the discrepancy. [ref]

So why are some people carrying the mutation that is supposed to cause CJD, yet they don’t seem to have the disease? That is one question researchers are still trying to answer.

Another question also floating around is whether other neurodegenerative diseases are really a type of prion disease.

Alzheimer’s and Parkson’s – 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 disease.[ref]  (Unfortunately, the article is behind a paywall so I can’t link to the full study.)

Let me summarize the background information on Alzheimer’s and Parkinson’s and then explain the link to prion pathology.

Alzheimer’s disease is the most common neurodegenerative disease and involves the accumulation of amyloid-beta plaque and tau protein tangles in the brain. The amyloid-beta accumulates extracellularly (outside the cell) in regions of the brain. Tau proteins normally support microtubule structures in the brain and elsewhere. In Alzheimer’s and other neurodegenerative diseases, the tau proteins form abnormal lesions in the brain.  Amyloid-β is a cleavage product of the amyloid precursor protein (APP).

Genetic mutations show how this happens. Rare, dominant mutations in the APP, PSEN1, or PSEN2 genes cause the hereditary early-onset form of Alzheimer’s disease. Tau protein is coded for by the MAPT gene; rare mutations of MAPT cause frontotemporal dementia.

Tau proteins that are abnormal also are implicated in CTE (from repeated concussions) and several other parkinsonian-like dementias.

Parkinson’s disease is the second most common neurodegenerative disease. It is characterized by tremors and motor movement problems and can also include dementia. The dopaminergic neurons in the substantia nigra region of the brain. This is caused by the protein α-synuclein being incorporated into insoluble fibers. Mutations in the SNCA gene, which codes for α-synuclein, cause a rare, hereditary, early-onset form of Parkinson’s.

Research now points to Alzheimer’s and Parkinson’s disease being similar to prion disease in a lot of ways. Similar to Creutzfeldt-Jakob Disease (CJD), most Alzheimer’s and Parkinson’s disease cases are sporadic – not caused by the rare mutations in the APP or SNCA genes.  The diseases all build insoluble proteins in the brain over the course of decades. And all cause neurodegenerative disease for which there is no cure.

One big difference, though, is that Alzheimer’s and Parkinson’s diseases are not considered to be transmissible or contagious, although some animal studies question this. Infectious sources of CJD (e.g. eating cow brains infected with mad cow) show that it can be passed from one source to another, although not everyone who eats infected meat (cow, deer, etc) gets the disease. And this infectiousness is 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 been found that decreases both 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]

If you would like to read more, here is a Scientific American article on the speculation that prions or prion-like proteins could be at the root of all neurodegenerative diseases. It explains that 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 show up in the brain.

More recently (June 2019 review article), research is linking together 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 early onset hereditary form 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.

Genetic variants involved in prion disease:

I’ve included these first two genetic variants to show that 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.  Kind of like buying two MegaMillion tickets to increase your odds of winning…  joking.

ZBTB38 gene:

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: normal

 

SEMA3A gene:

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: normal

PRNP gene:

The PRNP gene codes for the normal protein that when misfolded becomes a prion. There are several common genetic variants in this gene, and there are also rare mutations that cause familial CJD.

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

  • A/A: normal disease risk
  • A/G: reduced risk of sporadic 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]

The following are pathogenic prion disease mutations that can be found in 23andMe data. For prion diseases, you only need one copy of the mutation. I hesitate to even include these here… but I will with this caveat:   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.

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

  • C/C: normal
  • C/T: possible pathogenic allele for Gerstmann-Straussler-Scheinker syndrome (double check your genetic data with a clinical test) [ref]
Check your genetic data for rs28933385 (23andMe v4; AncestryDNA):

  • G/G: normal
  • A/G: E200K, possibly pathogenic allele for CJD, familial fatal insomnia, double check this with a clinical grade test [ref] [ref]
Check your genetic data for rs74315405 ( 23andMe v4 – i5004356; AncestryDNA ):

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

 

Lifehacks:

There are no magic cures or supplements to take to prevent or cure prion diseases, but you can take precautions not to eat prion-containing meat. There are laws now governing handling and feeding of cows as well as lots of testing in place to prevent the spread of mad cow disease. To be super cautious, avoid eating beef brains.

For hunters, this means being aware of whether chronic wasting disease is prevalent in your area if you are eating deer, elk, or moose meat. You can (and should!) get the meat tested before eating it in some areas of the US and Canada. https://cpw.state.co.us/learn/Pages/ResearchCWD.aspx

You can learn more and support prion research through the Prion Alliance, a 501(3)(c) non-profit run by researchers at the Broad Institute.

 

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