Protein Connections: A Network To Understand Disease

[Guest guest]

Protein Connections: A Network To Understand Disease

http://www.medicalnewstoday.com/medicalnews.php?newsid=43675

In the 1990s, the notion of " six degrees of separation " emphasized

human linkages that connected people around the world.

Now, the same concept provides clues to unraveling the mystery of how

different mutations in different genes can cause diseases with very

similar characteristics. In a paper in today's edition of the journal

Cell, scientists from Baylor College of Medicine and Harvard Medical

School describe a network of proteins that when perturbed by

mutations can result in ataxias, characterized by loss of balance and

coordination because of degeneration of specific nerve cells. The

concept can be used to study many diseases.

" We study degenerative diseases, " said Dr. Huda Zoghbi, professor of

molecular and human genetics, neurology, neuroscience and pediatrics

at BCM, a Medical Institute investigator and senior

author of the paper. " A gene is mutated, and a defective protein is

made. We need to know what proteins interact with it, and then we

study those interactions to learn how the mutant protein can damage

the neuron (or nerve cell). "

" A cell makes tens of thousands of proteins, " said Zoghbi. " One

protein interacts with many of them. How do you find all the proteins

that are relevant? "

She and the paper's first author, Dr. Janghoo Lim, a postdoctoral

trainee at BCM, decided instead to study all the proteins that, when

mutated, cause similar clinical problems, in this case ataxias.

" Perhaps the disease happens when these mutant proteins interact with

common partners, " she said.

To answer that question, Lim began to identify protein partners in

the Harvard laboratory of Dr. Marc Vidal, associate professor of

genetics and faculty member of the Dana Farber Cancer Institute.

" On the one hand, you have patients with diseases, and those diseases

look alike, like the ataxias, " said Vidal. " We are in the business of

understanding the wiring diagram of cells. In each cell, there are

20,000 to 25,000 proteins, and they interact with one another. We

know that many diseases are basically related back to mutations in

genes. But what if the whole network was perturbed in a way to cause

disease? "

" We picked 23 different disease genes to study, " said Lim.

All of them caused the same kind of degeneration in nerve cells, even

though they were different genes making different proteins.

" We felt they must have common protein partners, " he said.

" We found that the proteins made by those 23 genes all interacted

with one another, " said Zoghbi. " They either interacted directly or

indirectly through common partners. Proteins that we know can change

the course of disease in animal models were also identified as common

partners. "

" In this network are spots where many proteins interact, " she

said. " These are key proteins. "

These proteins, she said, could be extremely important in insuring

normal neuronal function.

" When you step back, you realize this is applicable to any human

disease, " she said. " You start with a handful of genes you know cause

disease and then go find their partners, and then their partners and

then build a network that will include all the factors that make you

susceptible to a disease or cause the symptoms of it. "

" Instead of thinking one gene-one disease, you realize that if there

are 10 genes that cause the same symptoms, they must do it through

some common pathways or interactions with other proteins. "

In applying the network theory to understanding disease, Zoghbi and

her colleagues have come full circle. Symptoms used to always be the

basis for medical treatment.

" Now we are providing a mechanistic basis for understanding why we

treat symptoms, " she said.

In the future, treatments may be designed to interrupt the cellular

missteps that lead to disease.

Others who participated in this research include: Drs. Chad Shaw,

Akash J. Patel and ph Fisk, of BCM, Drs. Gábor Szabó, Jean-

François Rual, Tong Hao, Ning Li, Smolyar, E. Hill and

Albert-László Barabási of Harvard. (Drs. Barabási and Szabó are now

at the University of Notre Dame.)