“Mind” your P(RPs) and Qs

Lemme tell you about Prion Diseases!

Photo by David Matos on Unsplash

I seem to have a knack for looking at the most bizarre things that can happen in nature and in the human body. You can imagine my excitement when I happened upon prion diseases, or prions, as they will be known in this here article.

What if I told you that pathogens are not limited to bacteria, viruses, and other virulent microbes? What if I told you that you could develop a deadly, incurable, infectious disease, purely by a protein in your brain deciding to perform some form of unorthodox molecular yoga? It is time to introduce you to prions. But, before we get into the nitty-gritty of these villainous proteins (and why they are so strange), we need to understand the inner workings of a protein. Grab a seat and have your neurologist on speed dial (not to check for prions) because your mind is about to get blown.

Proteins: what’s the big deal?

Proteins are complex structures made up of simple amino acid chains. These amino acids are coded for by the Deoxyribonucleic Acid (DNA) in the nucleus of your cells. An easy way to envision this process is to think of it as an order at a restaurant. You (the DNA) tell the wait staff [the messenger Ribonucleic Acid (RNA)] your order (a protein). The wait staff talk to the chefs (the ribosomal and transfer RNAs) which work together to assemble your order from the ingredients (the amino acids). Proteins come in a whole host of shapes and sizes. The shape of a protein is what determines its job in the body (Fig 1). Similarly, to how a qualification assures people that you know what you’re doing at your place of work; people trust that you can do your job well because you have the credentials to prove it. Proteins do almost everything in your body. There are certain conditions in that proteins cannot work. If it’s too cold, they become inactive, if it’s too warm, they can die in a process known as denaturation.

Fig 1: Proteins have varying shapes and sizes that allow them to do their functions properly. Figure obtained from the U.S. National Library of Medicine.

Prions: when proteins go bad.

Now that we understand how proteins are supposed to work, we can better appreciate how weird prions are. A neuroscientist by the name of Stanley Prusiner was awarded the Nobel Prize in Physiology or Medicine in 1997 after his discovery of prions. His interest in investigating prions began when a patient of his was slowly dying of a neurodegenerative disease known as Creutzfeldt–Jakob Disease (CJD). In his lecture on prions in 1998, he said the speed at which the disease killed her, by decimating her brain while her body was still completely healthy, was most impressive. Common diseases caused by prions in animals include scrapie in sheep and various other encephalopathic diseases such as mad cow disease. In humans, prion infection can lead to diseases such as Gerstmann-Straussler-Scheinker Syndrome, Fatal Familial Insomnia and Kuru.

Remember how we talked about the importance of the structure of proteins about two paragraphs ago? Well, prions result from a misfolded structure of the prion protein. Prions were previously thought to be a virus or bacteria, but experimentation showed that they were resistant to UV radiation, which hinted at their protein origin. To clear things up, prion proteins (PRPs) are usually good molecules. To differentiate the good PRPs from the bad ones; PRPC denotes the good protein (C means cellular), where PRPSc denotes the wonky protein (Sc means Scrapie). PRP is coded for by the Prnp gene on the DNA strand. This protein is thought to play a major role in brain function, particularly in cell signalling on the surface of the brain. Cell signalling is the process that allows cells to communicate with each other through the cell membrane. When you want to move your arm, cells in your muscles, bones and brain for example need to work in tandem to achieve this goal. A disruption in such a process can lead to motor dysfunction. Motor dysfunction simply means that you cannot move the way you want to move. But prions are not the only diseases that can result from protein misfolding; however, they are the only ones that are infectious. Alzheimer’s, Parkinson’s, Huntington’s, Type II diabetes as well as some forms of dementia are some of the most common diseases that result from this process. So how does misfolding happen?

In prions, the misfolding mechanism that results in PRPSc is thought be completely random. PRPCs are usually made up of lots of alpha-helices with a very low number of beta-sheets. Suddenly, the composition of these two compounds changes and now there are way more beta-sheets than there are alpha-helices (Fig 2). The increased number of beta-sheets are what makes PRP pathogenic, it has now become PRPSc. It’s like Norman Osborne becoming the Green Goblin when night falls: it’s still the same person (in this case, protein) just with a different look. As PRPC goes about its daily duties, as we’ve seen from the table, it can bind with other proteins to do this. They can unbind when the function is complete. This isn’t the case with PRPSc. This abnormal form can form clusters with one another, which can turn more normal PRPCs into PRPScs. PRPScs are also extremely hardy because of these increased beta-sheets and clustering. Heat cannot kill them, as heat does with normal proteins. Enzymes such as protease (which kills bad proteins anyway) cannot perform their function. These prions are indestructible. And this is how the prion disease is spread within the brain, as well as between organisms. Mad cow disease spread through cows being fed infected meat, and humans got it the same way. Kuru spread in cannibalistic tribes that consumed the brains of those that passed from Kuru (there’s a script for a zombie movie based on true events). If enough of these clusters form inside brain cells, it can result in programmed cell death (apoptosis). When enough cells die, the brain and its function deteriorate. This deterioration continues until the host dies. The complete structure of PRPSc is one that is not known either, so scientists are working extremely hard to figure this out and hopefully find a cure, not just for prions, but for the other neurodegenerative diseases as well.

Fig 2: The transformation of PRPC (left) to PRPSc(right). The red structures are the alpha-helices, and the green ones are the beta-sheets. This illustration shows how much bigger the beta-sheets can get, as well as increase in number when the PRP is transformed. Image from Gruszecka and Filip (2020).

Prions are scary. You can’t kill them, and as someone who most probably treasures your brain, it’s a sobering thought that one day your brain will essentially shrivel to nothing. Luckily for many of us, infectious prions are extremely rare under normal circumstances, unless you’ve suddenly developed a taste for BRAINS. If so, please keep your brain-eating habit to yourself. It’s only courteous that you mind your Ps and Qs.

Special thanks to L. Leal.

References:

Colby, D. W., & Prusiner, S. B. (2011). Prions. Cold Spring Harbor Perspectives in Biology, 3(1), a006833–a006833. Cold Spring Harbor Perspectives in Biology.

Kupfer, L., Hinrichs, W., & Groschup, M.. (2009). Prion Protein Misfolding. Current Molecular Medicine, 9(7), 826–835. Current Molecular Medicine.

Legname, G.. (2017). Elucidating the function of the prion protein. PLOS Pathogens, 13(8), e1006458. PLOS Pathogens.

Prusiner, S. B. (1998). Nobel Lecture: Prions. Proceedings of the National Academy of Sciences, 95(23), 13363–13383. Proceedings of the National Academy of Sciences.

Prusiner, S. B. (2001). Neurodegenerative Diseases and Prions. New England Journal of Medicine, 344(20), 1516–1526. New England Journal of Medicine.

Somero, G.N. (1995). Proteins and Temperature. Annual Review of Physiology(57), 43–68. Annual Review of Physiology.

Weissmann, C., Enari, M., Klöhn, P., Rossi, D., & Flechsig, E. (2002). Transmission of Prions. The Journal of Infectious Diseases, 186(s2), S157–S165. The Journal of Infectious Diseases.