Should've been more careful around prions...

When I say that prions are one of the coolest biological phenomena in existence, I mean to say that they are one of the most sci-fi and potentially frightening things you could encounter. They are the causative agent behind mad cow disease, which you’ve probably heard of, and which might not seem too terrifying. But the way prions work, and the fact that there is a “human form” of mad cow disease, will be enough to give you the creeps.

Did I mention that prion infection is the closest thing there is to real-life zombie-ism? Okay, okay, what IS a prion?

So, there are viruses, which are responsible for the flu, and there are bacteria, which cause tuberculosis; these are well-known. Even the lesser-known protists, which give rise to malaria, are similar to bacteria (although more complex in structure). Prions, on the other hand, are an altogether different infectious agent.

In simple terms, a prion is an rebellious protein, a protein that has failed to fold up into the proper configuration. And prions take their frustration out on normal proteins by making them fold up improperly, too, thus propagating more prions. In fact, the word “prion” is a contraction of “protein” and “infection.” How do prions work? Not by any means so taxing as invading a cell and hijacking its DNA, or anything like that. As far as we know, normal proteins fall prey to prions simply by physical contact, thus leading to a domino effect of prion creation, which I have tried to illustrate below (afterwards, I’ll show why prion infection is really, really bad).

Let’s say we start with 20 blissful blue proteins, and they’re blissful because each one of them is a nice square shape:

But then a vindictive prion comes along, and it’s angry because it failed at being a square (and because it has a unibrow):

 So this prion, like a real class act, takes its feelings out on the nearest normal protein by making contact with it:

And what was a normal protein is now a disgruntled, misshapen prion:

It’s all downhill from here. Two angry prions become four:

Four become eight:

And finally everybody is an angry, bent out of shape (literally) prion:

So why does prion infection matter? And what was I saying about zombies? This is where things get interesting.

As it turns out, cells do not like being full of misfolded proteins. The real problem with prion proteins is that they get tangled up and stick together, forming very large, stable aggregates inside of cells. This leads to cell death and tissue damage, specifically in the brain, where prions wreak their havoc. The picture below on the left shows a brain suffering from prion infection, riddled with holes due to tissue destruction (normal brain tissue is shown on the right at a lower magnification):

The effect of prions on the brain is also visible on a macroscopic scale, as seen in these brain sections where the prion-infected brain is on the left and is visibly deteriorated:

When a cow is infected with prions, it has mad cow disease. When a human is infected with prions, he/she has Creutzfeldt-Jakob disease (CJD; not as catchy). The symptoms of CJD start with dementia (memory/personality loss), followed by speech impairment, jerky movements, and poor balance (not to be insensitive, but this could all describe a zombie, no?)

There are three main ways you can end up with CJD: 1) acquire it, by somehow getting prions into your system from the environment, 2) inherit a mutation that dooms your proteins to become prions, or 3) have the bad luck to spontaneously develop prions in your brain.

Fore tribe members

While some people worry about eating beef when mad cow disease breaks out, you would have to consume beef that had picked up traces of brain and prion during processing in order to get CJD. What’s more, this and all  other acquired forms of human prion diseases make up less than one percent of cases. But since I’m on the topic, I’ll briefly mention that there is a tribe in Papua New Guinea called the Fore tribe, and in the 1950s they had an epidemic of a prion disease called kuru. This happened because it was traditional in this culture to eat the bodies (including the brains) of deceased family members. All it would’ve taken was one person with prion disease to die, then the family would’ve eaten prion-infected brain, which would eventually cause all of them to die, and then be eaten…and so on, until cannibalism was banned later in the ’50s. (Eating brains, developing zombie-like symptoms…the connections are hard to ignore.)

So the #1 rule if you don’t want to acquire prion disease is to not eat brains. Unfortunately, the vast majority (85%) of human prion diseases apparently arise sporadically, perhaps from some spontaneous mutation or conversion of normal protein to prion protein. Researchers say there is no amount of prions too small to cause full-blown disease, and once you’re affected there’s no cure and it’s always fatal. The only real variable is that it can take years of incubation before prion levels rise to symptom-causing levels.

I don’t mean to scare you! Despite all this, a human with prion disease is statistically one in a million. If anything, this post will hopefully prove useful to you the next time you’re in the company of nerdy friends, watching zombie movies, and you can sound extra nerdy: a lot of movies depicting a zombie apocalypse rely on the spread of zombie-ism through an aggressive virus, so when that tidbit comes up in the movie, you can turn to your friends and say, “Well, this would be more realistic if the virus precipitated prion formation….”

Stay nerdy!

(Side note: I threw in Max Brooks’s World War Z because it’s one of the best novels I’ve read in recent years — a surprisingly sobering and somehow realistic take on a post-zombie apocalypse world. Also, Patient Zero is the first book in a series that I adore by Jonathan Maberry; this book seriously brings hand-to-hand zombie combat to life.)

 

 

Trevitt CR, & Singh PN (2003). Variant Creutzfeldt-Jakob disease: pathology, epidemiology, and public health implications. The American journal of clinical nutrition, 78 (3 Suppl) PMID: 12936961

Edgeworth JA, Gros N, Alden J, Joiner S, Wadsworth JD, Linehan J, Brandner S, Jackson GS, Weissmann C, & Collinge J (2010). Spontaneous generation of mammalian prions. Proceedings of the National Academy of Sciences of the United States of America, 107 (32), 14402-6 PMID: 20660771

Fryer HR, & McLean AR (2011). There is no safe dose of prions. PloS one, 6 (8) PMID: 21858197

These researchers exploit this tryptophan-neurodegeneration link to make headway in finding better treatments for neurodegenerative diseases.

Title: Kynurenine 3-monooxygenase inhibition in blood ameliorates neurodegeneration

Authors: Daniel Zwilling, Shao-Yi Huang, Korrapati V. Sathyasaikumar, Francesca M. Notarangelo, Paolo Guidetti, Hui-Qiu Wu, Jason Lee, Jennifer Truong, Yaisa Andrews-Zwilling, Eric W. Hsieh, Jamie Y. Louie, Tiffany Wu, Kimberly Scearce-Levie, Christina Patrick, Anthony Adame, Flaviano Giorgini, Saliha Moussaoui, Grit Laue, Arash Rassoulpour, Gunnar Flik, Yadong Huang, Joseph M. Muchowski, Eliezer Masliah, Robert Schwarcz and Paul J. Muchowski

Date of publication: June 6, 2011

Direct link: http://www.sciencedirect.com/science/article/pii/S0092867411005812

PMID: 21640374

Abstract: When the amino acid tryptophan is broken down by the body, a metabolite called kynurenine is produced, and this metabolite also goes on to be broken down into other products. One of the products of kynurenine breakdown is kynurenic acid, which is thought to have a protective effect on the brain and is decreased in those with neurodegenerative disease. The authors of this paper synthesized a drug called JM6 that inhibits the enzyme responsible for breaking down kynurenic acid – theoretically this drug would allow kynurenic acid levels to remain high and provide continued neuroprotection. In mouse models of Alzheimer’s and Huntington’s, administration of JM6 led to fewer memory deficits and longer lifespans, among other improvements in brain function.

Methods: These researchers first developed “slow release” versions of a drug already known to increase kynurenic acid levels by inhibiting the enzyme responsible for kynurenic acid breakdown. Slow-release drugs remain in blood circulation for an extended time and are thought to be more effective for that reason; the slow-release drug tested in this paper is called JM6. In mice known to have Alzheimer’s or Huntington’s like conditions, JM6 was given daily before the onset of disease symptoms. At 6-7 months of age, mice were behaviorally assessed (e.g. by time spent completing a maze) and some mice were sacrificed in order to study changes in brain tissue.

Results: In short, the drug JM6 works quite well in mouse models of both Alzheimer’s and Huntington’s Diseases, as evidenced by better spatial memory and longer lives in mice treated with the drug compared to mice that did not receive treatment. Alzheimer’s mice that were receiving JM6 were about 10% better at performing maze tasks than mice who did not receive the drug, which was a statistically significant difference. These mice also showed a more appropriate response to anxiety-inducing situations, which is important because in human Alzheimer’s cases, patients often display social and/or sexual “disinhibition” stemming from a loss of anxiety responses. Lastly, the mice modeling Huntington’s Disease lived significantly longer (on the order of a few weeks) with JM6 treatment than without. Both the Alzheimer’s and the Huntington’s mice treated with JM6 showed healthier brain tissue, e.g. an undiminished number of synapses, which are responsible for sending messages between cells in the brain.

Bottom line: In mice (not humans!) fated to develop Alzheimer’s and Huntington’s-like symptoms, the drug JM6 worked convincingly well to improve mental condition. Whether or not this drug could work in humans remains to be seen, but this research is powerful because the authors know that the drug JM6 works by increasing the amount of kynurenine in the blood (recall: kynurenine is a product of breaking down the amino acid tryptophan). This means that a potentially new approach to finding treatments for Alzheimer’s and/or Huntington’s could be to develop more drugs that act by increasing the body’s levels of kynurenine; and knowing what to target with a drug is often the first step to creating an effective treatment.

Zwilling D, Huang SY, Sathyasaikumar KV, Notarangelo FM, Guidetti P, Wu HQ, Lee J, Truong J, Andrews-Zwilling Y, Hsieh EW, Louie JY, Wu T, Scearce-Levie K, Patrick C, Adame A, Giorgini F, Moussaoui S, Laue G, Rassoulpour A, Flik G, Huang Y, Muchowski JM, Masliah E, Schwarcz R, & Muchowski PJ (2011). Kynurenine 3-monooxygenase inhibition in blood ameliorates neurodegeneration. Cell, 145 (6), 863-74 PMID: 21640374