A Smell Protein that Can Kill

Mad Cow Protein Lets Mice (and Maybe You) Smell Well

Scientists identified the protein involved in mad cow disease quite a while ago. It is called protease resistant protein or PrP. What scientists hadn't figured out is what this protein does when it is working right. Until now that is.

A new study shows that, at least in mice, PrP is important for how well a mouse smells. In other words, it helps mice to tell different odors apart or smell certain smells. (It doesn't mean that it helps a mouse smell fresh...)

It may seem weird that a protein involved in smell could be so devastating. People with mad cow disease lose their memory and coordination and ultimately die.

But PrP makes more sense as a cause of these symptoms because smell doesn't just happen in the nose. It is processed in the brain. So if a brain protein like PrP goes bad, it can affect other parts of the brain too. And maybe even eventually kill someone.

Mad Cow Disease is a Prion Disease

People get mad cow disease
by eating cattle that have
a bad version of PrP.

Mad-cow disease is often in news headlines across the world. The disease is passed to humans when they eat meat from diseased cows. It is fatal, and after a person is infected, it may be years before they know they have it.

When a person eats an infected cow, their PrP changes shape. This changed PrP forms clumps or aggregates in the brain. These clumps build up and kill brain cells.

Mad-cow is very similar to other prion diseases that happen to lots of different kinds of mammals from sheep to cats to humans. All attack the brain, are fatal and work through PrP.

Getting Rid of PrP in Mice

Scientists decided to use mice to study PrP for a number of reasons. First, their Prp protein is very similar to the human protein. Second, mice get a kind of mad cow disease when their PrP isn't working well. Third, mice and people are not all that different in terms of their genes (about 99% of genes found in humans are also found in mice). Finally, mice are easy to work with genetically.

The genetics part is important because like all proteins, the instructions for PrP come from a gene. In this case the gene is called Prnp. One of the easiest ways to get an idea about how a protein works is to remove its gene from an animal.

It's like trying to figure out how a car works by taking out its parts. For example if a mechanic takes the engine out of a car, it won't run. This means that the engine is important for running the car. This is exactly what scientists did with PrP. They removed the Prnp gene and looked at what happened to the mouse.

At first removing or "knocking out" Prnp seemed to do very little. More experiments showed that the knockout mice had odd sleep patterns and problems learning. This new study showed that the mice did worse on a number of smell tests.

Prnp Knock Out Mice Can't Find Cookies

Scientists started out by asking if these mice could find a cookie. Basically they hid a cookie under the bedding of a mouse and saw how long it took the mouse to find it. Because the only way the mouse can find the cookie is by smell, this tests how good their sense of smell is.

Normal mice were able find the cookie on average in 73 seconds. However, Prnp knockout mice took on average 233 seconds! And they didn't even do it this well. The mice were given a maximum of 600 seconds to find the cookie and 6 out of 20 knockout mice never found it.

To make sure it was really smell that the Prnp knockout mice had trouble with, the scientists ran some other tests. They tested whether the knockout mice could move okay by placing the cookie on top of the bedding. They did just as well finding the cookie as the normal mice.

To make sure they had the same appetite as the normal mice, they tested how much the mice ate and weighed. The knockout mice were just the same as the normal mice. They also watched how fast they ate the cookie when they found it. The knockouts ate just as fast as the normal mice.

Additionally, the scientists made sure that the knockout mice explored as much as the normal mice. The knockout mice went to different parts of the cage just as much as the normal mice did.

So it seems that the Prnp knockout mice had a faulty sense of smell. Their olfactory systems just didn't work the same as a typical mouse's.

Peanut Butter Test

To confirm that the knockout mouse's sense of smell wasn't working quite right, the scientists tried another type of odor test. First the mice were presented with a peanut butter odor. The mice investigated the smell and then the smell was taken away. This happened 4 times in a row.

Normal mice and knockout mice do the same thing in this situation. They spend less and less time checking out the peanut butter smell each time it's given. The mice are probably curious at first with this new smell but each time later they become less and less interested.

But then the mice were given a new odor: a mix of peanut butter and vanilla. The normal mice were curious about the new odor and spent a lot of time with the mixed smell. The PrP knockout mice were not interested. They spent as little time with this new odor as they did with the 4th peanut butter odor. Most likely they could not smell the vanilla in the peanut butter.

The same thing happened when a new fruity smell was given to the mice. The normal mice were interested and spent much more time than the knockout mice.

The best explanation for these results is that something is wrong with the way these mice are able to smell. The cookie test showed that they can't smell as well as normal mice. And the peanut butter test shows that they can't tell the difference between new smells and old smells. To really test this idea the scientists took it one step further.

More Information

Mice without Prp can't
smell a hidden cookie.

Testing Smell Cells

In order for a person or a mouse to smell something, it uses a part of the brain called the olfactory bulb. The bulb is made of neurons, which are specialized nerve cells. These smell cells, like other neurons, talk to each other and other parts of the brain with an electrical signal.

If something is wrong in the mouse brain so that they can't smell well, then it should be found in these smell cells. So that's what the scientists tested. They measured the electrical signals in these cells to see if they were working right when given a smell. Compared to normal mice, the knockout mice had less powerful but longer signaling in these cells.

These tests show that mice without the Prnp gene have problems smelling what's around them. This is strong evidence that the PrP protein in normal mice plays a role in proper smelling. It will be interesting to see in the future if PrP also helps humans smell. Scientists also might be able to make a connection between what happens in mad cow disease and what the normal PrP protein does in the brain.

George Wang

Smell doesn't just happen
in the nose. The brain is
importnat in smell too.