Re: How do Prions cause Bovine Spongiform Encephalopathy (BSE)?

Your question is a very straightforward one, but I’m sorry to say there isn’t a straightforward answer. There are a lot of unanswered questions about how prions cause disease, and still some debate as to whether they even do cause disease. But I think that most scientists agree with the basic concepts that follow.

First, let’s be clear that Bovine Spongiform Encephalopathy (BSE) is just an example of a general class of diseases known as the spongiform encephalopathies. Other classic examples are a human disease called Creutzfeldt-Jakob Disease (CJD) and a sheep disease called scrapie. They are called "spongiform" because the brain of an affected person or animal literally looks like a sponge, i.e. with lots of little holes, when looked at under a microscope. This is the end result of the rapid and massive neurodegeneration that occurs, i.e. the loss of nerve cells and associated responses. This degeneration is clearly what causes the basic symptoms of all these diseases, namely rapidly progressive dementia (loss of cognitive function) and seizures. But why does it occur? The best model right now is that all of these diseases are cause by prions.

So what is a prion? This is a term that was coined to describe an infectious protein. Classically, transmissible agents that cause disease, i.e. infectious agents, include bacteria, fungi and viruses. One basic feature of all of these agents is that they have some form of a nucleic acid genome, i.e. a DNA or RNA molecule that tells how to make the essential proteins for that agent. But since some fairly early work with the spongiform encephalopathies, there has been the suggestion that the infectious agent of these diseases is only protein, i.e. it has no DNA or RNA component. At first this was considered heretical - how could you transmit information without DNA or RNA? Proteins were seen as "building blocks", not as carriers of the kind of information that was presumably needed to transmit a disease.

This is a very active area of research, but I would summarize the current thinking about prions as follows: the "infectious" prion protein is felt to be an abnormally folded version of a protein that is normally found in your body, called PrP. In other words, it is a single protein chain that is just put together in an unusual way. Think of a protein as a string that can be tied into a knot. Normally, a given protein string only gets tied into a certain kind of knot. But the prion protein can, under some circumstances, get tied into a slightly different kind of knot.

The abnormally folded or knotted version of the prion protein has some unusual and remarkable characteristics. First, it is extremely stable, surviving conditions that would destroy most proteins. Second, it seems to have the ability to cause other normally folded prion proteins to adopt the abnormal folding pattern. That last point is the key. Imagine that some abnormally folded prion protein got into your brain. Since it appears to be able to cause the normal protein to become abnormal, i.e. through propagation of an abnormal structure, you can imagine that over time you would start to have an accumulation of the abnormal protein in your brain.

How could that abnormally folded protein get into your brain to start with? Well, you could come in contact with the brain of a person or animal that has an accumulation of abnormal protein in their brain. Once it found its way to your brain (?by eating it?), the slow process of accumulation could begin. Otherwise, some PrP in your brain may just spontaneously fold abnormally, i.e. by itself. In fact, there are some human mutations that can cause this abnormal transition to happen with increased frequency, leading to inherited forms of CJD that do not require exposure to an infected person.

In the end, there is a lot of evidence to support the notion that the infectious prion agents act by the transmission of an abnormal protein structure, but this is not yet formally proven. Even if you accept this hypothesis, it still falls short of explaining how prion proteins actually cause neurological disease! In other words, why does an accumulation of abnormally folded prion protein cause neurodegeneration? There is no clear answer to this question yet. It does not appear to be due to loss of function of the normally folded protein. Instead, it seems more likely that the abnormal protein is in some way toxic, causing neurons to die or make ineffective and inappropriate connections. The one thing that is certain is that the brain eventually becomes highly disorganized in its activity, and to degenerate physically, which signals the beginning of the end.

Thanks for the question.

Tom Wilson, MD PhD