Prions as Microbes
Prion diseases have long fascinated biologists, because of the unusual nature of the infectious agent. Recently, prion diseases have become a major news story because of the emergence of the bovine (cow) prion disease BSE, which can be transmitted to humans as the disease vCJD.
Prions are infectious agents that long defied some of our basic ideas of biology. They appear to behave like other infectious organisms, yet they lack any of the most fundamental features of organisms. In particular, they lack any genetic material (DNA or RNA). Over time, work on prions has suggested that the “infectious agent” is actually a mis folded protein — which causes a normal cellular protein to change its shape to the misfolded form.
Prion diseases and prions are so unusual and so fascinating that they have been the subject of two Nobel prizes in Physiology or Medicine. In 1976 Carleton Gajdusek shared the Nobel prize for his work showing that the human disease kuru was similar to the well known sheep disease scrapie. In 1997 Stanley Prusiner, at UCSF, was the sole recipient of the prize; Prusiner was responsible for developing the modern prion model.
As diseases, prion diseases are quite rare and difficult to transmit. But they are also quite scary, because they are progressive neurodegenerative diseases, with no cure or treatment. They also have the mystique of being strange, due to the poor understanding of what prions are and how they work.
The prion disease most in the news is BSE (bovine spongiform encephalopathy), often called mad-cow disease. It is rather likely that the BSE agent can be transmitted to humans, and cause vCJD (variant Creutzfeldt-Jakob disease). The number of known vCJD cases in humans is under 200, but there are so many unknowns, including a possible incubation period of many years, that this mysterious disease strikes fear — at least much uncertainty.
As we learn more about prion diseases, a new part of the story is emerging. It is possible that a number of neurodegenerative diseases long considered quite distinct may share some underlying features. These include Alzheimer’s disease, Parkinson’s disease, Huntington disease, and the prion diseases. The common thread may be that all involve misfolded proteins. The reason for the mis-folding and the details of the disease development vary, and there is no implication here that all of these are infectious. In fact, not all prion diseases are infectious.
Prion diseases are typically slowly developing neurodegenerative diseases. The classic prion diseases are found in mammals. However, prion-type phenomena have been found in yeast, as discussed below. Thus we should be open to the possibility of finding prion phenomena, good or bad, which are different from the neurodegenerative diseases that we usually discuss.
Here are some of the more common prion diseases you are likely to hear about. In general, these diseases are fairly specific to one type of animal, so they are listed by animal.
Scrapie is the “classic” prion disease and the subject of most early work on this type of disease. Sheep are not very good lab animals, so progress was slow. Scrapie has been adapted to small lab animals, including mice and hamsters; much lab work is done with mouse scrapie or hamster scrapie.
BSE (bovine spongiform encephalopathy) is the big one in the news
CJD (Creutzfeldt-Jakob Disease)
vCJD (variant Creutzfeldt-Jakob Disease). This is a distinct disease from CJD; it is almost certainly caused by the agent that causes BSE in cattle.
Less common but reasonably well-characterized prion diseases in humans include: FFI (fatal familial insomnia) and GSS (Gerstmann-Straussler-Scheinker syndrome)
Elk and deer
CWD (chronic wasting disease)
The Prion: the infectious agent
Some prion disease appears to be infectious. That is, one can isolate something from an infected individual, give it to another individual and that individual will get the disease and make more of the infectious material. This is the behavior one expects for an infectious agent, such as a virus or bacterium. (Microbiologists would say that the prion infectious agent satisfies Koch’s postulates, a set of groundrules used to show that one has an infectious agent. So what kind of an infectious agent is it? This is the step at which the biologists get very fascinated with the prion. The properties of the infectious agent do not correspond to those of any known agent. In particular…
- * The prion agent is not inactivated by a wide range of treatments that should inactivate viruses or bacteria.
- * The prion agent, so far as we can tell, contains no nucleic acid — no genome.
Now, prion infectious material is not easy to handle, and early experiments showing these properties were subject to challenge. However, further work continued to support these properties. Thus it seemed that the prion agent was not an ordinary agent. In fact, it almost seemed that the prion agent was a self-replicating protein. The problem is that “a self-replicating protein” does not fit with our modern understanding of proteins. “A self-replicating protein” would be a major violation of the “Central Dogma”, which says that only nucleic acids can “self-replicate”. This is why biologists have been fascinated by the prion agent. If it really did what it seemed to do, it would reveal a major weakness in our understanding of genes and proteins.
Two major developments have served to bring some clarity to the nature of the prion agent. We discuss these in the following two sections. At that point, we will present the current working model for the nature of the prion agent — a model which is now widely accepted, yet has still not been clearly shown to be correct.
The prion gene
At some point the gene that codes for the prion protein was found. Where? In the host. That is, the prion gene — the gene for the prion protein — is a normal host gene. When a sheep gets a prion disease (scrapie), the sheep’s own gene for the prion protein codes for any new prion protein that is produced.