BSE, Scrapie, CJD and the Prion Protein
BSE (Bovine Spongiform Encephalopathy, also known as Mad Cow Disease), scrapie, and CJD (Creutzfeldt-Jakob-Disease) are three closely related dementia diseases of cows, sheep, and humans. They are much in the news because of the likelihood that the disease can pass from one species to others, maybe via food from sheep to cows and from cows to humans. The disease does not seem to be due to a virus, bacterium, or fungus (mold), but rather to a somewhat surprising protein, called the prion protein. This protein corresponds to a gene naturally found in the genome of all vertebrates from human to fish.
The normal role of this protein in the nervous system is not yet known. The gene is small, it typically consists of 771 nucleotides (that makes 771/3 = 257 amino acids). It is expressed in many, but not all, tissues of the animal, always on the outside surface of the cell membrane. The gene has been sequenced from about 70 species in an attempt to understand what differences in sequence and structure underlie species barriers.
You can obtain the sequence for your favorite species by visiting
GenBank
and entering 'prion'.
(After hitting the ``Search''
button, click next on the ``Retrieve XXX Documents''
button. Then click around...)
It is quite interesting to obtain the sequences for 4-6 species and align them in
color.
(Just copy-paste your sequences, or the ones
below, into the big box of the
ClustalW form,
and switch the ``COLOR'' button to ``yes''. Click here for a screenshot.)
In the next image you can see the result:
Notice how similar all 4 sequences are!
A lot more analysis can be done with prion sequences using a wide variety
of online tools.
The 3-dimensional structure of mouse prion has been largely determined and is seen in the next snapshot. Keep an eye on the helical structure on the left!
The way the prion protein is thought to be infectious is as follows: There are two stable conformations, good and bad. These are the same in terms of covalent bonds, but differ in their secondary and tertiary structural conformation. The bad conformer has the ability to recruit the good conformer, making two bad conformers. Then these two go out and recruit still more. Bad conformers are retained in a growing fiber. When this gets large, oxidative damage results, followed by neuronal cell loss, followed by development of holes (spongiform encephalopathy). This leads to coma and death; the process can take decades overall. Now here's an animation of the changes that probably take place if a good conformer turns into a bad one.
The disease in humans, called Creutzfeldt-Jakob Disease, was first recognized in the early 1920's. Jakob's first patient had the inherited form of the disease due to a point mutation (aspartic acid to asparagine) in the prion gene at position 178. Other mutations are known today at 18 other positions, all on chromosome 20. About 85% of the cases are called 'sporadic' -- which means the cause is not known. And sometimes the disease can be acquired from medical procedures, e.g. from traces of the infective agent from a previous patient during brain surgery. It is also clear that in some cases, this disease can be transmitted by diet from one species to another. There are about 27 cases in humans as of September 1997 where the transmission of the BSE agent to a human, causing CJD, is strongly suspected.
There may be a large number of neurological diseases involving different genes that have the same underlying disease architecture. They would not necessarily be transmitted through diet like BSE because their good conformer might not be accessible on the cell surface of a neuron, like the prion protein: it cannot be ``found'' by the bad conformer. Much more work is needed before anyone can be sure how it all will turn out. At this point, there is no treatment of any kind.
Wanna know more? PubMed is a good site to visit for summaries of the latest research; sometimes there is commentary and research gossip available too, along with government viewpoints. There is new prion research published almost every week in Nature, Science, and PNAS. Color graphics from these articles and others generated directly from the protein coordinates have been collected in a prion Image Gallery. However, it is more fun to view the prion protein in interactive 3D -- this allows it to be instantly viewed from any angle. Links to free software viewers and the interactive files themselves are also available from the Image Gallery.