Worm Protein: Clue to Kidney Disease?
by Michael Campbell
To
learn about human kidney disease, Matthew Buechner uses a worm so small
that it doesn't even have a kidney.
Buechner, a University of Kansas assistant professor
of molecular biosciences, and his colleagues study the genetic disorder
polycystic kidney disease, or PKD. PKD can cause the fist-sized kidney
to balloon to the dimensions of a football.
Buechner said that he and his colleagues have found
that the tiny roundworm Caenorhabditis (see-no-rab-DIE-tis) elegans
has proteins remarkably similar to those that malfunction in PKD. By
studying these proteins, they hope to better understand how the disease
operates in people.
In PKD, some of the kidney's tiny blood-filtering tubes,
called nephrons, swell into large, fluid-filled cysts.
A normal nephron is thinner than a human hair and about
as long as the thumb. A nephron afflicted with PKD may expand into a
cyst the size of a marble or even a baseball.
Eventually, the cysts break free and clog the kidney,
causing it to fail. The only treatment is replacement of the damaged
organ.
The National Institutes of Health says that about 500,000
Americans have the disease. It is one of the most common serious genetic
illnesses in the country, affecting more people than muscular dystrophy,
cystic fibrosis, ALS, and sickle-cell anemia combined.
Mutations in one of two genes cause the disease, but
no one knows why the proteins made by the faulty genes cause cysts.
Buechner hopes to change that by studying the protein from the threadlike,
soil-dwelling roundworm, which is just big enough to see without a microscope.
"Understanding what is happening with this protein
in worms will give us a better understanding of what is happening in
humans," he said, "From the resemblance of the proteins, we predict
that a lot of the things that are happening in worm cells also in human
cells."
Buechner and his colleagues have presented their results
at the last two meetings of the American Society of Nephrology.
Now, they hope to figure out exactly how the proteins
work in the worms, and then use that information to figure out how they
work in humans.
Surprisingly, Buechner said, the big evolutionary distance
between the worms and humans can make information obtained from the
worms especially valuable.
"It is useful to compare the same genes from humans
and distant creatures because that gives you a hint as to where the
very basic core of the gene is," he said, "The areas that are similar
between the worms and humans are likely to be the areas most crucial
to the function of that protein."
Despite their structural similarity, the worm and human
proteins have very different jobs.
In humans, the proteins control the diameter of the
nephrons and are found throughout the kidney and at other locations
in the body.
In worms, the proteins have a sensory role and are
only found in the nervous system of males. They help the males find
the vulvas of their bisexual partners (there are no females) during
mating.
It may seem strange that such similar proteins can
have such divergent tasks. However, Buechner said he believes the proteins
function in somewhat similar ways as they go about those tasks.
In both worms and humans, the proteins reside in the
membranes that mark a cell's outer boundary. And in both worms and humans,
part of the protein projects from the membrane.
These projections help male worms sense a vulva. In
humans their function is unknown, Buechner said.
He noted, however, that the projections stick out into
the waste fluid flowing through the tubes filtering the blood and that
the diameter of these tubes changes continuously throughout a person's
lifetime.
Thus, Buechner believes that the PKD protein might
sense the flow of fluid in a blood-filtering tube and adjust the tube's
diameter accordingly.
The idea has not been proved, he said.
Buechner said PKD is common because it is an autosomal
dominant disease -- that is, someone only needs one copy of the bad
gene to show symptoms. Most genetic diseases are autosomal recessive,
meaning someone must have two bad copies to get the disease.
Despite its frequency, Buechner said PKD is not well-known
because people do not feel its effects until relatively late in life.
"You don't even know you have it until you start having
pain in your back from your kidney enlarging in your 30's or 40's or
even later," he said. "It's a serious disease, but a very subtle one."
Michael Campbell is a student in the KU School of
Journalism.
