Small-scale research taking aim at disease

Small-scale research taking aim at disease

BY CAROLYNE PARK

Posted on Sunday, April 26, 2009


University of Arkansas at Little Rock researchers are examining Parkinson's disease at its most fundamental level in hopes of finding a way to stop the progression of the debilitating disease.

Chemistry professor Jerry Darsey and doctoral student Sushma Thotakura are leading the one-year study that's being paid for with the help of a grant from the Michael J. Fox Foundation for Parkinson's Research.

Darsey, who's been at UALR since 1990, said the research is focused on addressing the disease in its earliest stages.

"Most of the treatments for Parkinson's right now are looking at the symptoms, not the cause," Darsey said. "We're attacking it from a molecular point of view."

But the team isn't working in a traditional laboratory or spending hours bent over microscopes, cell samples or petri dishes.

Instead, they're using advanced computer programs that can generate models of molecules and predict how they would interact with proteins in the brain linked to the disease.

First characterized by an English doctor named James Parkinson in 1817, Parkinson's disease is a chronic and progressive brain disorder that affects about 1 in 100 people older than 60, according to the National Parkinson Foundation.

An estimated 1.5 million Americans have the disease, and 60,000 new cases are diagnosed annually. About 15 percent of cases are diagnosed in people younger than 50.

People with Parkinson's can have a variety of symptoms, including uncontrollable shaking of a hand or limb, stiffness, slowed movement, muffled speech, difficulty with balance, depression and limited facial expression.

While there's still a lot to learn about Parkinson's, scientists know there's a strong link to genetics, Darsey said. Something in a person's genetic code causes errors in a protein called alpha-synuclein, causing it to become warped.

The malformed proteins gather together, forming abnormal clumps in a part of the brain called the substantia nigra, which plays an important role in controlling body movement.

The clumps - called Lewy bodies - block some of the brain's nerve cells, also called neurons, causing them to die or become damaged.

"Over time this prevents the neurons from producing the molecules they need to do their job," Darsey said.

That job is to generate dopamine, a chemical that allows communication between the substantia nigra and neurons higher in the brain. If enough neurons are damaged, a person's motor functions are affected and he develops the symptoms of Parkinson's disease.

Through their research, Darsey and Thotakura hope to find a molecule that will attach to the alpha-synuclein protein and either prevent it from becoming malformed or revert it back to a normal shape after it's been malformed.

If scientists can find a molecule to do one of those two things, they can prevent the proteins from damaging neurons in the brain and thus stop progression of the disease.

"Once a brain cell dies, there's no getting them back," Darsey said.

MODELING MOLECULES

While he specializes in molecular modeling and has worked in biomedical research before, Darsey said this is his first time working with Parkinson's disease.

He and Thotakura will use three computer programs for the project. Those programs will allow them to use what they know about existing molecules to generate models of new molecules that no one's ever built before.

They will then be able to use those models to predict how the molecules would interact with alpha-synuclein proteins in the brain.

Using computers, they can run tests on hundreds or thousands of molecules in a fraction of the time it would take to build the molecules in a laboratory, Darsey said.

"It takes months or years to synthesize a molecule," Darsey said. "We can do it as fast as we can run the program."

But they face several challenges in finding just the right type of molecule for the job, said Jon Wilkes, research chemist at the National Center for Toxicological Research in Jefferson, near Pine Bluff. Wilkes is an adviser on the UALR project, along with Dan Buzatu, a fellow research chemist at the center.

The first challenge is finding molecules of the right shape or structure to fit into receptors in the alpha-synuclein protein. They'll then have to study how each potential molecule would interact or bond with the protein.

If they find ones that have one of the two desired effects - to either prevent or reverse the protein's malformation - they have a third obstacle, Wilkes said.

The molecules must be able to pass through what is known as the "blood-brain barrier," a natural defense system that prevents certain chemicals and other molecules in the blood from passing into brain tissue.

Even a molecule able to revert the protein's malformation won't do any good for Parkinson's patients if the brain rejects it, Wilkes said.

If they find molecules that meet all the criteria, those should then be made and tested by pharmaceutical companies as potential treatments for Parkinson's disease, Wilkes said.

THE GRANT

The Michael J. Fox Foundation is providing a one-year $75,000 grant through its Research Rapid Response Innovation Awards program for Darsey and Thotakura to do their work. UALR is providing $25,000 more in funding and in-kind support.

Since it was founded in late 2000, the foundation has provided more than $142 million for Parkinson's research around the globe.

The foundation started the Rapid Response program in 2007 to provide seed money for scientists to start research, said Kirsten Carlson, the foundation's associate director of research programs.

"It operates on a rolling deadline, so if somebody has a great idea at any time during the year they have a mechanism to apply for funding from us," she said. "The focus is really on high risk but potentially high reward projects with the potential for significant impact in understanding of the disease or treatment for Parkinson's."

Todd Sherer, the foundation's vice president of research, said, "The idea is to allow the scientist, while that idea is fresh and exciting in their mind, to get some real-time support."

The grants are no more than $75,000 for one year. After a year, if the research is promising enough, the foundation will consider further funding.

One such project by researchers at Northwestern University in Evanston, Ill., studied whether a common high blood pressure medication also had the ability to protect neurons in the brain.

The Rapid Response grant allowed researchers to test their hypothesis in the laboratory. Positive results there led to an additional $2 million grant from the foundation, which is allowing them to test the drug on Parkinson's patients.

But even projects that don't lead to more research are valuable in furthering overall knowledge of the disease, Sherer said.

"It's OK for us if some of them end up testing their hypothesis and it doesn't pan out but it got tested in a rigorous way," he said. "We see that as being successful."

Carlson said the foundation has funded about 30 projects a year through its Rapid Response program, and only a handful of those go on to get additional funding.

Darsey and Thotakura's grant funding started in January and ends at the end of the year.

This winter, they'll present the results of their study at the Michael J. Fox Foundation in New York. Depending on what they find, they may apply for additional funding at that time.

As with all Parkinson's research, it's about taking little steps toward finding better treatments and ultimately a cure, Darsey said.

"We're making a lot of progress, but there's still a lot of progress to be made," he said.